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1. Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold

Author

Ghosh, Ujjayini, Tse, Eric, Yang, Hyunjun, Shi, Marie, Caro, Christoffer D, Wang, Feng, Merz, Gregory E, Prusiner, Stanley B, Southworth, Daniel R, and Condello, Carlo

Subjects
Biochemistry and Cell Biology, Biological Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Brain Disorders, Dementia, Neurodegenerative, Neurosciences, Down Syndrome, Aging, Alzheimer's Disease, Intellectual and Developmental Disabilities (IDD), 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, tau Proteins, Cryoelectron Microscopy, Middle Aged, Alzheimer Disease, Female, Adult, Male, Neurofibrillary Tangles, Brain, Down syndrome, Alzheimer's disease, Tauopathy, Protein conformation, Cryo-electron microscopy, Alzheimer’s disease, Cryo–electron microscopy, Clinical Sciences, Biochemistry and cell biology
Abstract

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

Published
2024

3. The p97/VCP adaptor UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions

Author

Braxton, Julian R, Altobelli, Chad R, Tucker, Maxwell R, Tse, Eric, Thwin, Aye C, Arkin, Michelle R, and Southworth, Daniel R

Subjects
Biochemistry and Cell Biology, Biological Sciences, Underpinning research, 1.1 Normal biological development and functioning, Humans, Valosin Containing Protein, Protein Binding, Protein Structure, Tertiary, Cell Cycle Proteins, Chemical Sciences, Medical and Health Sciences, Biophysics, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

p97, also known as valosin-containing protein, is an essential cytosolic AAA+ (ATPases associated with diverse cellular activities) hexamer that unfolds substrate polypeptides to support protein homeostasis and macromolecular disassembly. Distinct sets of p97 adaptors guide cellular functions but their roles in direct control of the hexamer are unclear. The UBXD1 adaptor localizes with p97 in critical mitochondria and lysosome clearance pathways and contains multiple p97-interacting domains. Here we identify UBXD1 as a potent p97 ATPase inhibitor and report structures of intact human p97-UBXD1 complexes that reveal extensive UBXD1 contacts across p97 and an asymmetric remodeling of the hexamer. Conserved VIM, UBX and PUB domains tether adjacent protomers while a connecting strand forms an N-terminal domain lariat with a helix wedged at the interprotomer interface. An additional VIM-connecting helix binds along the second (D2) AAA+ domain. Together, these contacts split the hexamer into a ring-open conformation. Structures, mutagenesis and comparisons to other adaptors further reveal how adaptors containing conserved p97-remodeling motifs regulate p97 ATPase activity and structure.

Published
2023

5. Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments

Author

Merz, Gregory E, Chalkley, Matthew J, Tan, Sophia K, Tse, Eric, Lee, Joanne, Prusiner, Stanley B, Paras, Nick A, DeGrado, William F, and Southworth, Daniel R

Subjects
Biochemistry and Cell Biology, Biological Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Neurosciences, Brain Disorders, Bioengineering, Alzheimer's Disease, Neurodegenerative, Dementia, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Neurological, Humans, Alzheimer Disease, Amyloid, Cryoelectron Microscopy, Ligands, tau Proteins
Abstract

Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.

Published
2023

7. Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.

Author

Cupo, Ryan R, Rizo, Alexandrea N, Braun, Gabriel A, Tse, Eric, Chuang, Edward, Gupta, Kushol, Southworth, Daniel R, and Shorter, James

Subjects
Humans, Nucleotides, Ankyrins, Heat-Shock Proteins, Adenosine Triphosphate, Protein Transport, Models, Molecular, AAA+ proteins, protein aggregation, CP: Cell biology, chaperone, disaggregase, mitochondria, mitochondrial disorders, therapeutics, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, Biochemistry and Cell Biology, Medical Physiology
Abstract

The AAA+ protein, Skd3 (human CLPB), solubilizes proteins in the mitochondrial intermembrane space, which is critical for human health. Skd3 variants with defective protein-disaggregase activity cause severe congenital neutropenia (SCN) and 3-methylglutaconic aciduria type 7 (MGCA7). How Skd3 disaggregates proteins remains poorly understood. Here, we report a high-resolution structure of a Skd3-substrate complex. Skd3 adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers. Deleting the ANK linker region reduces dodecamerization and disaggregase activity. We elucidate apomorphic features of the Skd3 NBD and C-terminal domain that regulate disaggregase activity. We also define how Skd3 subunits collaborate to disaggregate proteins. Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. These advances illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns, and suggest therapeutic strategies.

Published
2022

12. 36-month clinical outcomes of patients with venous thromboembolism: GARFIELD-VTE

Author

Loualidi, Ab, Colak, Abdurrahim, Bezuidenhout, Abraham, Abdool-Carrim, Abu, Azeddine, Addala, Beyers, Adriaan, Dees, Adriaan, Mohamed, Ahmed, Aksoy, Ahmet, Abiko, Akihiko, Watanabe, Akinori, Krichell, Alan, Fernandez, Alberto Alfredo, Tosetto, Alberto, Khotuntsov, Alexey, Oropallo, Alisha, Slocombe, Alison, Kelly, Allan, Clark, Amanda, Gad, Amr, Arouni, Amy, Schmidt, Andor, Berni, Andrea, Kleiban, Andres Javier, Machowski, Andrew, Kazakov, Andrey, Galvez, Angel, Lockman, Ann, Falanga, Anna, Chauhan, Anoop, Riera-Mestre, Antoni, Mazzone, Antonino, D'Angelo, Armando, Herdy, Artur, Kato, Atsushi, Salem, Ayman Abd Elhamid Ebrahim Mahmoud, Husin, Azlan, Erdelyi, Barbara, Jacobson, Barry, Amann-Vesti, Beatrice, Battaloglu, Bektas, Wilson, Benedicte, Cosmi, Benilde, Francois, Bergmann Jean, Toufek, Berremeli, Hunt, Beverley, Natha, Bhavesh, Mustafa, Bisher, Kho, Bonnie Chi Shan, Carine, Boulon, Zidel, Brian, Dominique, Brisot, Christophe, Brousse, Trimarco, Bruno, Luo, Canhua, Cuneo, Carlos Alberto, Diaz, Carlos Jerjes Sanchez, Schwencke, Carsten, Cader, Cas, Yavuz, Celal, Zaidman, Cesar Javier, Lunn, Charles, Wu, Chau-Chung, Toh, Cheng Hock, Chiang, Chern-En, Elisa, Chevrier, Hsia, Chien-Hsun, Huang, Chien-Lung, Kwok, Chi-Hang Kevin, Wu, Chih-Cheng, Huang, Chi-Hung, Ward, Chris, Opitz, Christian, Jeanneret-Gris, Christina, Ha, Chung Yin, Huang, Chun-Yao, Bidi, Claude Luyeye, Smith, Clifford, Brauer, Cornelia, Lodigiani, Corrado, Francis, Couturaud, Wu, Cynthia, Staub, Daniel, Theodoro, Daniel, Poli, Daniela, Acevedo, David - Riesco, Adler, David, Jimenez, David, Keeling, David, Scott, David, Imberti, Davide, Creagh, Desmond, Helene, Desmurs-Clavel, Hagemann, Dirk, Le Roux, Dirk, Skowasch, Dirk, Belenky, Dmitry, Dorokhov, Dmitry, Petrov, Dmitry, Zateyshchikov, Dmitry, Prisco, Domenico, Møller, Dorthe, Kucera, Dusan, Esheiba, Ehab M., Panchenko, Elizaveta, Dominique, Elkouri, Dogan, Emre, Kubat, Emre, Diaz, Enrique Diaz, Tse, Eric Wai Choi, Yeo, Erik, Hashas, Erman, Grochenig, Ernst, Tiraferri, Eros, Blessing, Erwin, Michèle, Escande Orthlieb, Usandizaga, Esther, Porreca, Ettore, Ferroni, Fabian, Nicolas, Falvo, Ayala-Paredes, Félix, Koura, Firas, Henry, Fitjerald, Cosmi, Franco, Erdkamp, Frans, Kamalov, Gadel, Dalmau, Garcia-Bragado, Damien, Garrigues, Klein, Garry, Shah, Gaurand, Hollanders, Geert, Merli, Geno, Plassmann, Georg, Platt, George, Poirier, Germain, Sokurenko, German, Haddad, Ghassan, Ali, Gholam, Agnelli, Giancarlo, Gan, Gin Gin, Kaye-Eddie, Grace, Le Gal, Gregoire, Allen, Gregory, Esperón, Guillermo Antonio Llamas, Jean-Paul, Guillot, Gerofke, Hagen, Elali, Hallah, Burianova, Hana, Ohler, Hans-Juergen, Wang, Haofu, Darius, Harald, Gogia, Harinder S., Striekwold, Harry, Gibbs, Harry, Hasanoglu, Hatice, Turker, Hatice, Franow, Hendrik, Bounameaux, Henri, De Raedt, Herbert, Schroe, Herman, ElDin, Hesham Salah, Zidan, Hesham, Nakamura, Hiroaki, Kim, Ho Young, Lawall, Holger, Zhu, Hong, Tian, Hongyan, Yhim, Ho-Young, ten Cate, Hugo, Hwang, Hun Gyu, Shim, Hyeok, Kim, Igor, Libov, Igor, Sonkin, Igor, Suchkov, Igor, Song, Ik-Chan, Kiris, Ilker, Staroverov, Ilya, Looi, Irene, De La Azuela Tenorio, Isabel M., Savas, Ismail, Gordeev, Ivan, Podpera, Ivo, Lee, Jae Hoon, Sathar, Jameela, Welker, James, Beyer-Westendorf, Jan, Kvasnicka, Jan, Vanwelden, Jan, Kim, JangYong, Svobodova, Jaromira, Gujral, Jaspal, Marino, Javier, Galvar, Javier Tristan, Kassis, Jeannine, Kuo, Jen-Yuan, Shih, Jhih-Yuan, Kwon, JiHyun, Joh, Jin Hyun, Park, Jin Hyun, Kim, Jin Seok, Yang, Jinghua, Krupicka, Jiri, Lastuvka, Jiri, Pumprla, Jiri, Vesely, Jiri, Souto, Joan Carlos, Correa, João Antônio, Duchateau, Johan, Fletcher, John Perry, del Toro, Jorge, Paez, Jorge Guillermo Chavez, Nielsen, Jørn, Filho, Jose Dalmo Araujo, Saraiva, Jose, Peromingo, Jose Antonio Diaz, Lara, Jose Gomez, Fedele, Jose Luis, Surinach, Jose Maria, Chacko, Joseph, Muntaner, Juan Antonio, Benitez, Juan Carlos Álvarez, Abril, Juan Moreno Hoyos, Humphrey, Julian, Bono, Julio, Kanda, Junji, Boondumrongsagoon, Juree, Yiu, Kai Hang, Chansung, Kanchana, Boomars, Karin, Burbury, Kate, Kondo, Katsuhiro, Karaarslan, Kemal, Takeuchi, Kensuke, Kroeger, Knut, Zrazhevskiy, Konstantin, Svatopluk, Koscál, Shyu, Kou-Gi, Vandenbosch, Kristel, Chang, Kuan-Cheng, Chiu, Kuan-Ming, Jean-Manuel, Kubina, Wern, Kwan Jing, Ueng, Kwo-Chang, Norasetthada, Lalita, Binet, Laure, Chew, Lee Ping, Zhang, Lei, Cristina, Leone Maria, Tick, Lidwine, Schiavi, Lilia Beatriz, Wong, Lily Lee Lee, Borges, Lohana, Botha, Louis, Capiau, Luc, Timmermans, Luc, López, Luciano Eduardo, Ria, Luigi, Blasco, Luis Manuel Hernandez, Guzman, Luis Alberto, Cervera, Luis Flota, Isabelle, Mahe, Bosch, Manuel Monreal, de los Rios Ibarra, Manuel, Fernandez, Manuel Núñez, Carrier, Marc, Barrionuevo, Marcelo Raul, Gamba, Marco Antonio Alcocer, Cattaneo, Marco, Moia, Marco, Bowers, Margaret, Chetanachan, Mariam, Berli, Mario Alberto, Fixley, Mark, Faghih, Markus, Stuecker, Markus, Schul, Marlin, Banyai, Martin, Koretzky, Martin, Myriam, Martin, Gaffney, Mary Elizabeth, Hirano, Masao, Kanemoto, Masashi, Nakamura, Mashio, Tahar, Mersel, Emmanuel, Messas, Kovacs, Michael, Leahy, Michael, Levy, Michael, Munch, Michael, Olsen, Michael, De Pauw, Michel, Gustin, Michel, Van Betsbrugge, Michiel, Boyarkin, Mikhail, Homza, Miroslav, Koto, Modise, Abdool-Gaffar, Mohamed, Nagib, Mohamed Ayman Fakhry, El-Dessoki, Mohamed, Khan, Mohamed, Mohamed, Monniaty, Kim, Moo Hyun, Lee, Moon-Hee, Soliman, Mosaad, Ahmed, Mostafa Shawky, el Bary, Mostafa Soliman Abd, Moustafa, Moustafa A., Hameed, Muhammad, Kanko, Muhip, Majumder, Mujibur, Zubareva, Nadezhda, Mumoli, Nicola, Abdullah, Nik Azim Nik, Makruasi, Nisa, Paruk, Nishen, Kanitsap, Nonglak, Duda, Norberto, Nordin, Nordiana, Nyvad, Ole, Barbarash, Olga, Gurbuz, Orcun, Vilamajo, Oscar Gomez, Flores, Oscar Nandayapa, Gur, Ozcan, Oto, Oztekin, Marchena, Pablo Javier, Angchaisuksiri, Pantep, Carroll, Patrick, Lang, Pavel, MacCallum, Peter, von Bilderling, Peter Baron, Blombery, Peter, Verhamme, Peter, Jansky, Petr, Bernadette, Peuch, De Vleeschauwer, Philippe, Hainaut, Philippe, Ferrini, Piera Maria, Iamsai, Piriyaporn, Christian, Ponchaux, Viboonjuntra, Pongtep, Rojnuckarin, Ponlapat, Ho, Prahlad, Mutirangura, Pramook, Wells, Rachel, Martinez, Rafael, Miranda, Raimundo Tirado, Kroening, Ralf, Ratsela, Rapule, Reyes, Raquel Lopez, de Leon, Raul Franco Diaz, Wong, Raymond Siu Ming, Alikhan, Raz, Jerwan-Keim, Reinhold, Otero, Remedios, Murena-Schmidt, Renate, Canevascini, Reto, Ferkl, Richard, White, Richard, Van Herreweghe, Rika, Santoro, Rita, Klamroth, Robert, Mendes, Robert, Prosecky, Robert, Cappelli, Roberto, Spacek, Rudolf, Singh, Rupesh, Griffin, Sam, Na, Sang Hoon, Chunilal, Sanjeev, Middeldorp, Saskia, Nakazawa, Satoshi, Schellong, Sebastian, Toh, See Guan, Christophe, Seinturier, Isbir, Selim, Raymundo, Selma, Ting, Seng Kiat, Motte, Serge, Aktogu, Serir Ozkan, Donders, Servaas, Cha, Seung Ick, Nam, Seung-Hyun, Marie-Antoinette, Sevestre-Pietri, Maasdorp, Shaun, Sun, Shenghua, Wang, Shenming, Essameldin, Sherif Mohamed, Sholkamy, Sherif Mohamed, Kuki, Shintaro, Goto, Shinya, Yoshida, Shuichi, Matsuoka, Shunzo, McRae, Simon, Watt, Simon, Patanasing, Siriwimon, Jean-Léopold, Siwe-Nana, Wongkhantee, Somchai, Bang, Soo-Mee, Testa, Sophie, Zemek, Stanislav, Behrens, Steffen, Dominique, Stephan, Mellor, Stuart, Singh, Suaran Singh Gurcharan, Datta, Sudip, Chayangsu, Sunee, Solymoss, Susan, Everington, Tamara, Abdel-Azim, Tarek Ahmed Adel, Suwanban, Tawatchai, Adademir, Taylan, Hart, Terence, Béatrice, Terriat, Luvhengo, Thifhelimbilu, Horacek, Thomas, Zeller, Thomas, Boussy, Tim, Reynolds, Tim, Biss, Tina, Chao, Ting-Hsing, Casabella, Tomas Smith, Onodera, Tomoya, Numbenjapon, Tontanai, Gerdes, Victor, Cech, Vladimir, Krasavin, Vladimir, Tolstikhin, Vladimir, Bax, W.A., Malek, Wagih Fawzy Abdel, Ho, Wai Khoon, Ageno, Walter, Pharr, Walter, Jiang, Weihong, Lin, Wei-Hsiang, Zhang, Weihua, Tseng, Wei-Kung, Lai, Wen-Ter, De Backer, Wilfried, Haverkamp, Wilhelm, Yoshida, Winston, Korte, Wolfgang, Choi, Won Il, Kim, Yang-Ki, Tanabe, Yasuhiro, Ohnuma, Yasushi, Mun, Yeung-Chul, Balthazar, Yohan, Park, Yong, Shibata, Yoshisato, Burov, Yuriy, Subbotin, Yuriy, Coufal, Zdenek, Yang, Zhenwen, Jing, Zhicheng, Yang, Zhongqi, Turpie, Alexander G.G., Farjat, Alfredo E., Haas, Sylvia, Weitz, Jeffrey I., Goldhaber, Samuel Z., Kayani, Gloria, Lopes, Renato D., Tse, Eric, Muntaner, Juan, Prandoni, Paolo, Maheshwari, Uma, and Kakkar, Ajay K.

Published
2023
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13. The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state

Author

Lee, Kanghyun, Thwin, Aye C, Nadel, Cory M, Tse, Eric, Gates, Stephanie N, Gestwicki, Jason E, and Southworth, Daniel R

Subjects
Biochemistry and Cell Biology, Biological Sciences, Underpinning research, 1.1 Normal biological development and functioning, Amino Acid Sequence, Binding Sites, Biomarkers, Tumor, Cryoelectron Microscopy, HSP90 Heat-Shock Proteins, Humans, Molecular Chaperones, Molecular Conformation, Protein Binding, Tacrolimus Binding Proteins, Tumor Protein, Translationally-Controlled 1, FKBP51, Hsp90, cryo-electron microscopy, heat shock proteins, immunophilins, molecular chaperones, p23, peptidyl-prolyl isomerase, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during folding of kinases, nuclear receptors, and tau. Here we determined the cryoelectron microscopy (cryo-EM) structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å, which, together with mutagenesis and crosslinking analyses, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent to Hsp90 client binding sites, whereas a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 is positioned to act on specific client residues presented during Hsp90-catalyzed remodeling.

Published
2021

14. CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes

Author

Gupta, Meghna, Azumaya, Caleigh M, Moritz, Michelle, Pourmal, Sergei, Diallo, Amy, Merz, Gregory E, Jang, Gwendolyn, Bouhaddou, Mehdi, Fossati, Andrea, Brilot, Axel F, Diwanji, Devan, Hernandez, Evelyn, Herrera, Nadia, Kratochvil, Huong T, Lam, Victor L, Li, Fei, Li, Yang, Nguyen, Henry C, Nowotny, Carlos, Owens, Tristan W, Peters, Jessica K, Rizo, Alexandrea N, Schulze-Gahmen, Ursula, Smith, Amber M, Young, Iris D, Yu, Zanlin, Asarnow, Daniel, Billesbølle, Christian, Campbell, Melody G, Chen, Jen, Chen, Kuei-Ho, Chio, Un Seng, Dickinson, Miles Sasha, Doan, Loan, Jin, Mingliang, Kim, Kate, Li, Junrui, Li, Yen-Li, Linossi, Edmond, Liu, Yanxin, Lo, Megan, Lopez, Jocelyne, Lopez, Kyle E, Mancino, Adamo, Moss, Frank R, Paul, Michael D, Pawar, Komal Ishwar, Pelin, Adrian, Pospiech, Thomas H, Puchades, Cristina, Remesh, Soumya Govinda, Safari, Maliheh, Schaefer, Kaitlin, Sun, Ming, Tabios, Mariano C, Thwin, Aye C, Titus, Erron W, Trenker, Raphael, Tse, Eric, Tsui, Tsz Kin Martin, Wang, Feng, Zhang, Kaihua, Zhang, Yang, Zhao, Jianhua, Zhou, Fengbo, Zhou, Yuan, Zuliani-Alvarez, Lorena, Consortium, QCRG Structural Biology, Agard, David A, Cheng, Yifan, Fraser, James S, Jura, Natalia, Kortemme, Tanja, Manglik, Aashish, Southworth, Daniel R, Stroud, Robert M, Swaney, Danielle L, Krogan, Nevan J, Frost, Adam, Rosenberg, Oren S, and Verba, Kliment A

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Pneumonia, Emerging Infectious Diseases, Biodefense, Vaccine Related, Infectious Diseases, Prevention, Pneumonia & Influenza, Lung, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Infection, Generic health relevance
Abstract

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

Published
2021

15. Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY

Author

Chatzikonstantinou, Thomas, Scarfò, Lydia, Karakatsoulis, Georgios, Minga, Eva, Chamou, Dimitra, Iacoboni, Gloria, Kotaskova, Jana, Demosthenous, Christos, Smolej, Lukas, Mulligan, Stephen, Alcoceba, Miguel, Al-Shemari, Salem, Aurran-Schleinitz, Thérèse, Bacchiarri, Francesca, Bellido, Mar, Bijou, Fontanet, Calleja, Anne, Medina, Angeles, Khan, Mehreen Ali, Cassin, Ramona, Chatzileontiadou, Sofia, Collado, Rosa, Christian, Amy, Davis, Zadie, Dimou, Maria, Donaldson, David, Santos, Gimena Dos, Dreta, Barbara, Efstathopoulou, Maria, El-Ashwah, Shaimaa, Enrico, Alicia, Fresa, Alberto, Galimberti, Sara, Galitzia, Andrea, García-Serra, Rocío, Gimeno, Eva, González-Gascón-y-Marín, Isabel, Gozzetti, Alessandro, Guarente, Valerio, Guieze, Romain, Gogia, Ajay, Gupta, Ritu, Harrop, Sean, Hatzimichael, Eleftheria, Herishanu, Yair, Hernández-Rivas, José-Ángel, Inchiappa, Luca, Jaksic, Ozren, Janssen, Susanne, Kalicińska, Elżbieta, Laribi, Kamel, Karakus, Volkan, Kater, Arnon P., Kho, Bonnie, Kislova, Maria, Konstantinou, Eliana, Koren-Michowitz, Maya, Kotsianidis, Ioannis, Kreitman, Robert J., Labrador, Jorge, Lad, Deepesh, Levin, Mark-David, Levy, Ilana, Longval, Thomas, Lopez-Garcia, Alberto, Marquet, Juan, Martin-Rodríguez, Lucia, Maynadié, Marc, Maslejova, Stanislava, Mayor-Bastida, Carlota, Mihaljevic, Biljana, Milosevic, Ivana, Miras, Fatima, Moia, Riccardo, Morawska, Marta, Murru, Roberta, Nath, Uttam Kumar, Navarro-Bailón, Almudena, Oliveira, Ana C., Olivieri, Jacopo, Oscier, David, Panovska-Stavridis, Irina, Papaioannou, Maria, Papajík, Tomas, Kubova, Zuzana, Phumphukhieo, Punyarat, Pierie, Cheyenne, Puiggros, Anna, Rani, Lata, Reda, Gianluigi, Rigolin, Gian Matteo, Ruchlemer, Rosa, Daniel de Deus Santos, Marcos, Schipani, Mattia, Schiwitza, Annett, Shen, Yandong, Simkovic, Martin, Smirnova, Svetlana, Abdelrahman Soliman, Dina Sameh, Spacek, Martin, Tadmor, Tamar, Tomic, Kristina, Tse, Eric, Vassilakopoulos, Theodoros, Visentin, Andrea, Vitale, Candida, von Tresckow, Julia, Vrachiolias, George, Vukovic, Vojin, Walewska, Renata, Wasik-Szczepanek, Ewa, Xu, Zhenshu, Yagci, Munci, Yañez, Lucrecia, Yassin, Mohamed, Zuchnicka, Jana, Angelopoulou, Maria, Antic, Darko, Biderman, Bella, Catherwood, Mark, Claus, Rainer, Coscia, Marta, Cuneo, Antonio, Demirkan, Fatih, Espinet, Blanca, Gaidano, Gianluca, Kalashnikova, Olga B., Laurenti, Luca, Nikitin, Eugene, Pangalis, Gerassimos A., Panagiotidis, Panagiotis, Popov, Viola Maria, Pospisilova, Sarka, Sportoletti, Paolo, Stavroyianni, Niki, Tam, Constantine, Trentin, Livio, Chatzidimitriou, Anastasia, Bosch, Francesc, Doubek, Michael, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2023
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16. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2

Author

Azumaya, Caleigh M, Braxton, Julian R, Brilot, Axel F, Gupta, Meghna, Li, Fei, Lopez, Kyle E, Melo, Arthur, Merz, Gregory E, Moss, Frank, Paulino, Joana, Pospiech, Thomas H, Pourmal, Sergei, Puchades, Cristina, Rizo, Alexandrea N, Smith, Amber M, Sun, Ming, Thomas, Paul V, Wang, Feng, Yu, Zanlin, Asarnow, Daniel, Campbell, Melody G, Chio, Cynthia M, Chio, Un Seng, Dickinson, Miles Sasha, Diwanji, Devan, Faust, Bryan, Hoppe, Nick, Jin, Mingliang, Li, Junrui, Liu, Yanxin, Nguyen, Henry C, Sangwan, Smriti, Trenker, Raphael, Trinidad, Donovan, Tse, Eric, Zhang, Kaihua, Zhou, Fengbo, Billesboelle, Christian, Bowen, Alisa, Li, Yen-Li, Nguyen, Phuong, Nowotny, Carlos, Safari, Mali, Schaefer, Kaitlin, Tsui, Tsz Kin Martin, Whitis, Natalie, Zhao, Jianhua, Kim, Kate, Moritz, Michelle, Owens, Tristan W, Peters, Jessica K, Biel, Justin, Deshpande, Ishan, Herrera, Nadia, Kratochvil, Huong T, Liu, Xi, Schulze-Gahmen, Ursula, Young, Iris D, Chen, Jen, Diallo, Amy, Doan, Loan, Flores, Sebastian, Lam, Victor L, Li, Yang, Lo, Megan, Thwin, Aye C, Titus, Erron W, Zhang, Yang, and Bulkley, David

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biodefense, Vaccine Related, Clinical Research, Prevention, Lung, Emerging Infectious Diseases, Infectious Diseases, Pneumonia & Influenza, Pneumonia, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Angiotensin-Converting Enzyme 2, Animals, Antibodies, Neutralizing, Antibodies, Viral, Binding Sites, Antibody, Chlorocebus aethiops, Cryoelectron Microscopy, HEK293 Cells, Humans, Models, Molecular, Peptide Library, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, SARS-CoV-2, Single-Chain Antibodies, Spike Glycoprotein, Coronavirus, Vero Cells, QCRG Structural Biology Consortium, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml-1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.

Published
2021

17. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

Author

Schoof, Michael, Faust, Bryan, Saunders, Reuben A, Sangwan, Smriti, Rezelj, Veronica, Hoppe, Nick, Boone, Morgane, Billesbølle, Christian B, Puchades, Cristina, Azumaya, Caleigh M, Kratochvil, Huong T, Zimanyi, Marcell, Deshpande, Ishan, Liang, Jiahao, Dickinson, Sasha, Nguyen, Henry C, Chio, Cynthia M, Merz, Gregory E, Thompson, Michael C, Diwanji, Devan, Schaefer, Kaitlin, Anand, Aditya A, Dobzinski, Niv, Zha, Beth Shoshana, Simoneau, Camille R, Leon, Kristoffer, White, Kris M, Chio, Un Seng, Gupta, Meghna, Jin, Mingliang, Li, Fei, Liu, Yanxin, Zhang, Kaihua, Bulkley, David, Sun, Ming, Smith, Amber M, Rizo, Alexandrea N, Moss, Frank, Brilot, Axel F, Pourmal, Sergei, Trenker, Raphael, Pospiech, Thomas, Gupta, Sayan, Barsi-Rhyne, Benjamin, Belyy, Vladislav, Barile-Hill, Andrew W, Nock, Silke, Liu, Yuwei, Krogan, Nevan J, Ralston, Corie Y, Swaney, Danielle L, García-Sastre, Adolfo, Ott, Melanie, Vignuzzi, Marco, Walter, Peter, Manglik, Aashish, Braxton, Julian R, Lopez, Kyle E, Melo, Arthur, Paulino, Joana, Pospiech, Thomas H, Thomas, Paul V, Wang, Feng, Yu, Zanlin, Dickinson, Miles Sasha, Asarnow, Daniel, Campbell, Melody G, Li, Junrui, Tsui, Tsz Kin Martin, Trinidad, Donovan, Tse, Eric, Zhou, Fengbo, Herrera, Nadia, and Schulze-Gahmen, Ursula

Subjects
Biochemistry and Cell Biology, Biological Sciences, Lung, Vaccine Related, Prevention, Infectious Diseases, Pneumonia, Pneumonia & Influenza, Biodefense, Emerging Infectious Diseases, Angiotensin-Converting Enzyme 2, Animals, Antibodies, Neutralizing, Antibodies, Viral, Antibody Affinity, Chlorocebus aethiops, Cryoelectron Microscopy, Humans, Neutralization Tests, Protein Binding, Protein Stability, Single-Domain Antibodies, Spike Glycoprotein, Coronavirus, Vero Cells, QCRG Structural Biology Consortium, General Science & Technology
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

Published
2020

18. Conformational plasticity of the ClpAP AAA+ protease couples protein unfolding and proteolysis

Author

Lopez, Kyle E, Rizo, Alexandrea N, Tse, Eric, Lin, JiaBei, Scull, Nathaniel W, Thwin, Aye C, Lucius, Aaron L, Shorter, James, and Southworth, Daniel R

Subjects
Biochemistry and Cell Biology, Biological Sciences, Generic health relevance, Adenosine Triphosphate, Cryoelectron Microscopy, DNA Helicases, Endopeptidase Clp, Escherichia coli, Escherichia coli Proteins, Models, Molecular, Multiprotein Complexes, Protein Conformation, Protein Unfolding, Trans-Activators, Chemical Sciences, Medical and Health Sciences, Biophysics, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

The ClpAP complex is a conserved bacterial protease that unfolds and degrades proteins targeted for destruction. The ClpA double-ring hexamer powers substrate unfolding and translocation into the ClpP proteolytic chamber. Here, we determined high-resolution structures of wild-type Escherichia coli ClpAP undergoing active substrate unfolding and proteolysis. A spiral of pore loop-substrate contacts spans both ClpA AAA+ domains. Protomers at the spiral seam undergo nucleotide-specific rearrangements, supporting substrate translocation. IGL loops extend flexibly to bind the planar, heptameric ClpP surface with the empty, symmetry-mismatched IGL pocket maintained at the seam. Three different structures identify a binding-pocket switch by the IGL loop of the lowest positioned protomer, involving release and re-engagement with the clockwise pocket. This switch is coupled to a ClpA rotation and a network of conformational changes across the seam, suggesting that ClpA can rotate around the ClpP apical surface during processive steps of translocation and proteolysis.

Published
2020

19. Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation

Author

Chen, John J, Nathaniel, Diane L, Raghavan, Preethi, Nelson, Maxine, Tian, Ruilin, Tse, Eric, Hong, Jason Y, See, Stephanie K, Mok, Sue-Ann, Hein, Marco Y, Southworth, Daniel R, Grinberg, Lea T, Gestwicki, Jason E, Leonetti, Manuel D, and Kampmann, Martin

Subjects
Biochemistry and Cell Biology, Biological Sciences, Aging, Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Dementia, Alzheimer's Disease, Neurosciences, Acquired Cognitive Impairment, Brain Disorders, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Rare Diseases, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Generic health relevance, Neurological, Cells, Cultured, Endosomal Sorting Complexes Required for Transport, HEK293 Cells, Humans, Lysosomes, Protein Aggregates, tau Proteins, CRISPR/Cas, Membrane damage, Tau protein, endosomal sorting complexes required for transport, endosome, fluorescence resonance energy transfer, functional genomics, lysosome, protein aggregation, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Intercellular propagation of protein aggregation is emerging as a key mechanism in the progression of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia (FTD). However, we lack a systematic understanding of the cellular pathways controlling prion-like propagation of aggregation. To uncover such pathways, here we performed CRISPR interference (CRISPRi) screens in a human cell-based model of propagation of tau aggregation monitored by FRET. Our screens uncovered that knockdown of several components of the endosomal sorting complexes required for transport (ESCRT) machinery, including charged multivesicular body protein 6 (CHMP6), or CHMP2A in combination with CHMP2B (whose gene is linked to familial FTD), promote propagation of tau aggregation. We found that knocking down the genes encoding these proteins also causes damage to endolysosomal membranes, consistent with a role for the ESCRT pathway in endolysosomal membrane repair. Leakiness of the endolysosomal compartment significantly enhanced prion-like propagation of tau aggregation, likely by making tau seeds more available to pools of cytoplasmic tau. Together, these findings suggest that endolysosomal escape is a critical step in tau propagation in neurodegenerative diseases.

Published
2019

20. Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity

Author

Lempart, Justine, Tse, Eric, Lauer, James A, Ivanova, Magdalena I, Sutter, Alexandra, Yoo, Nicholas, Huettemann, Philipp, Southworth, Daniel, and Jakob, Ursula

Subjects
Biochemistry and Cell Biology, Biological Sciences, Dementia, Neurosciences, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Parkinson's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Alzheimer's Disease, Aging, Prevention, Cell Line, Tumor, Cell Membrane, Extracellular Space, Humans, Polyphosphates, Protein Binding, Protein Multimerization, alpha-Synuclein, Biological sciences, Biomedical and clinical sciences
Abstract

The universally abundant polyphosphate (polyP) accelerates fibril formation of disease-related amyloids and protects against amyloid cytotoxicity. To gain insights into the mechanism(s) by which polyP exerts these effects, we focused on α-synuclein, a well-studied amyloid protein, which constitutes the major component of Lewy bodies found in Parkinson's disease. Here, we demonstrate that polyP is unable to accelerate the rate-limiting step of α-synuclein fibril formation but effectively nucleates fibril assembly once α-synuclein oligomers are formed. Binding of polyP to α-synuclein either during fibril formation or upon fibril maturation substantially alters fibril morphology and effectively reduces the ability of α-synuclein fibrils to interact with cell membranes. The effect of polyP appears to be α-synuclein fibril specific and successfully prevents the uptake of fibrils into neuronal cells. These results suggest that altering the polyP levels in the extracellular space might be a potential therapeutic strategy to prevent the spreading of the disease.

Published
2019

23. Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase.

Author

Rizo, Alexandrea N, Lin, JiaBei, Gates, Stephanie N, Tse, Eric, Bart, Stephen M, Castellano, Laura M, DiMaio, Frank, Shorter, James, and Southworth, Daniel R

Subjects
Escherichia coli, Endopeptidase Clp, Peptides, Escherichia coli Proteins, Caseins, Heat-Shock Proteins, Protein Subunits, Adenosine Triphosphate, Cryoelectron Microscopy, Protein Transport, Hydrolysis, Models, Molecular, Protein Aggregates, AAA Domain, Models, Molecular
Abstract

Bacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. Here we report cryo-EM structures of a hyperactive ClpB variant bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS, which reveal the translocation mechanism. Distinct substrate-gripping interactions are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent to the topmost NBD1 contact. NBD conformations at the seam interface reveal how ATP hydrolysis-driven substrate disengagement and re-binding are precisely tuned to drive a directional, stepwise translocation cycle.

Published
2019

24. Chaperone activation and client binding of a 2-cysteine peroxiredoxin.

Author

Teixeira, Filipa, Tse, Eric, Castro, Helena, Makepeace, Karl AT, Meinen, Ben A, Borchers, Christoph H, Poole, Leslie B, Bardwell, James C, Tomás, Ana M, Southworth, Daniel R, and Jakob, Ursula

Subjects
Leishmania infantum, Cysteine, Molecular Chaperones, Cryoelectron Microscopy, Protein Binding, Protein Folding, Peroxiredoxins
Abstract

Many 2-Cys-peroxiredoxins (2-Cys-Prxs) are dual-function proteins, either acting as peroxidases under non-stress conditions or as chaperones during stress. The mechanism by which 2-Cys-Prxs switch functions remains to be defined. Our work focuses on Leishmania infantum mitochondrial 2-Cys-Prx, whose reduced, decameric subpopulation adopts chaperone function during heat shock, an activity that facilitates the transition from insects to warm-blooded host environments. Here, we have solved the cryo-EM structure of mTXNPx in complex with a thermally unfolded client protein, and revealed that the flexible N-termini of mTXNPx form a well-resolved central belt that contacts and encapsulates the unstructured client protein in the center of the decamer ring. In vivo and in vitro cross-linking studies provide further support for these interactions, and demonstrate that mTXNPx decamers undergo temperature-dependent structural rearrangements specifically at the dimer-dimer interfaces. These structural changes appear crucial for exposing chaperone-client binding sites that are buried in the peroxidase-active protein.

Published
2019

25. Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau.

Author

Freilich, Rebecca, Betegon, Miguel, Tse, Eric, Mok, Sue-Ann, Julien, Olivier, Agard, David A, Southworth, Daniel R, Takeuchi, Koh, and Gestwicki, Jason E

Subjects
Humans, tau Proteins, Heat-Shock Proteins, Molecular Chaperones, Microscopy, Electron, Magnetic Resonance Spectroscopy, Protein Interaction Domains and Motifs, HSP27 Heat-Shock Proteins
Abstract

Small heat shock proteins (sHSPs) are a class of oligomeric molecular chaperones that limit protein aggregation. However, it is often not clear where sHSPs bind on their client proteins or how these protein-protein interactions (PPIs) are regulated. Here, we map the PPIs between human Hsp27 and the microtubule-associated protein tau (MAPT/tau). We find that Hsp27 selectively recognizes two aggregation-prone regions of tau, using the conserved β4-β8 cleft of its alpha-crystallin domain. The β4-β8 region is also the site of Hsp27-Hsp27 interactions, suggesting that competitive PPIs may be an important regulatory paradigm. Indeed, we find that each of the individual PPIs are relatively weak and that competition for shared sites seems to control both client binding and Hsp27 oligomerization. These findings highlight the importance of multiple, competitive PPIs in the function of Hsp27 and suggest that the β4-β8 groove acts as a tunable sensor for clients.

Published
2018

26. Polyphosphate Stabilizes Protein Unfolding Intermediates as Soluble Amyloid-like Oligomers

Author

Yoo, Nicholas G, Dogra, Siddhant, Meinen, Ben A, Tse, Eric, Haefliger, Janine, Southworth, Daniel R, Gray, Michael J, Dahl, Jan-Ulrik, and Jakob, Ursula

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurodegenerative, Amyloidogenic Proteins, Escherichia coli Proteins, Hot Temperature, L-Lactate Dehydrogenase, Oxidative Stress, Polyphosphates, Protein Multimerization, Protein Stability, Protein Unfolding, Solubility, Polyphosphate, heat shock, protein unfolding, amyloid-like aggregates, chaperone, Medicinal and Biomolecular Chemistry, Microbiology, Biochemistry & Molecular Biology, Biochemistry and cell biology
Abstract

Inorganic polyphosphate (polyP) constitutes one of the most conserved and ubiquitous molecules in biology. Recent work in bacteria demonstrated that polyP increases oxidative stress resistance by preventing stress-induced protein aggregation and promotes biofilm formation by stimulating functional amyloid formation. To gain insights into these two seemingly contradictory functions of polyP, we investigated the effects of polyP on the folding model lactate dehydrogenase. We discovered that the presence of polyP during the thermal unfolding process stabilizes folding intermediates of lactate dehydrogenase as soluble micro-β-aggregates with amyloid-like properties. Size and heterogeneity of the oligomers formed in this process were dependent on the polyP chain length, with longer chains forming smaller, more homogenous complexes. This ability of polyP to stabilize thermally unfolded proteins even upon exposure to extreme temperatures appears to contribute to the observed resistance of uropathogenic Escherichia coli toward severe heat shock treatment. These results suggest that the working mechanism of polyP is the same for both soluble and amyloidogenic proteins, with the ultimate outcome likely being determined by a combination of polyP chain length and the client protein itself. They help to explain how polyP can simultaneously function as general stress-protective chaperone and instigator of amyloidogenic processes in vivo.

Published
2018

31. X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition

Author

Cesa, Laura C, Shao, Hao, Srinivasan, Sharan R, Tse, Eric, Jain, Chetali, Zuiderweg, Erik RP, Southworth, Daniel R, Mapp, Anna K, and Gestwicki, Jason E

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Breast Cancer, Biotechnology, Generic health relevance, Biomarkers, Cell Line, Tumor, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Humans, Protein Binding, Proto-Oncogene Mas, X-Linked Inhibitor of Apoptosis Protein, cancer biology, chaperone, chemical biology, heat shock protein 90, protein–protein interaction, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Heat shock protein 70 (Hsp70) and Hsp90 are molecular chaperones that play essential roles in tumor growth by stabilizing pro-survival client proteins. However, although the development of Hsp90 inhibitors has benefited from the identification of clients, such as Raf-1 proto-oncogene, Ser/Thr kinase (RAF1), that are particularly dependent on this chaperone, no equivalent clients for Hsp70 have been reported. Using chemical probes and MDA-MB-231 breast cancer cells, we found here that the inhibitors of apoptosis proteins, including c-IAP1 and X-linked inhibitor of apoptosis protein (XIAP), are obligate Hsp70 clients that are rapidly (within ∼3-12 h) lost after inhibition of Hsp70 but not of Hsp90. Mutagenesis and pulldown experiments revealed multiple Hsp70-binding sites on XIAP, suggesting that it is a direct, physical Hsp70 client. Interestingly, this interaction was unusually tight (∼260 nm) for an Hsp70-client interaction and involved non-canonical regions of the chaperone. Finally, we also found that Hsp70 inhibitor treatments caused loss of c-IAP1 and XIAP in multiple cancer cell lines and in tumor xenografts, but not in healthy cells. These results are expected to significantly accelerate Hsp70 drug discovery by providing XIAP as a pharmacodynamic biomarker. More broadly, our findings further suggest that Hsp70 and Hsp90 have partially non-overlapping sets of obligate protein clients in cancer cells.

Published
2018

34. Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2

Author

Moffitt, Andrea B, Ondrejka, Sarah L, McKinney, Matthew, Rempel, Rachel E, Goodlad, John R, Teh, Chun Huat, Leppa, Sirpa, Mannisto, Susanna, Kovanen, Panu E, Tse, Eric, Au-Yeung, Rex KH, Kwong, Yok-Lam, Srivastava, Gopesh, Iqbal, Javeed, Yu, Jiayu, Naresh, Kikkeri, Villa, Diego, Gascoyne, Randy D, Said, Jonathan, Czader, Magdalena B, Chadburn, Amy, Richards, Kristy L, Rajagopalan, Deepthi, Davis, Nicholas S, Smith, Eileen C, Palus, Brooke C, Tzeng, Tiffany J, Healy, Jane A, Lugar, Patricia L, Datta, Jyotishka, Love, Cassandra, Levy, Shawn, Dunson, David B, Zhuang, Yuan, Hsi, Eric D, and Dave, Sandeep S

Subjects
Genetics, Cancer, Hematology, Lymphoma, Rare Diseases, Clinical Research, Biotechnology, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Animals, DNA Copy Number Variations, Enteropathy-Associated T-Cell Lymphoma, Female, Gene Expression Profiling, Gene Silencing, Histone-Lysine N-Methyltransferase, Humans, Male, Mice, Knockout, Middle Aged, Mutation, Sequence Analysis, DNA, T-Lymphocytes, Medical and Health Sciences, Immunology
Abstract

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

Published
2017

35. BAG3 Is a Modular, Scaffolding Protein that physically Links Heat Shock Protein 70 (Hsp70) to the Small Heat Shock Proteins

Author

Rauch, Jennifer N, Tse, Eric, Freilich, Rebecca, Mok, Sue-Ann, Makley, Leah N, Southworth, Daniel R, and Gestwicki, Jason E

Subjects
Underpinning research, Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Generic health relevance, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, DNA Mutational Analysis, HSP70 Heat-Shock Proteins, Heat-Shock Proteins, Small, Humans, Protein Binding, chaperones, Hsp27, proteostasis, intrinsically disordered proteins, protein folding, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Microbiology, Biochemistry & Molecular Biology
Abstract

Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that are important for binding and stabilizing unfolded proteins. In this task, the sHsps have been proposed to coordinate with ATP-dependent chaperones, including heat shock protein 70 (Hsp70). However, it is not yet clear how these two important components of the chaperone network are linked. We report that the Hsp70 co-chaperone, BAG3, is a modular, scaffolding factor to bring together sHsps and Hsp70s. Using domain deletions and point mutations, we found that BAG3 uses both of its IPV motifs to interact with sHsps, including Hsp27 (HspB1), αB-crystallin (HspB5), Hsp22 (HspB8), and Hsp20 (HspB6). BAG3 does not appear to be a passive scaffolding factor; rather, its binding promoted de-oligomerization of Hsp27, likely by competing for the self-interactions that normally stabilize large oligomers. BAG3 bound to Hsp70 at the same time as Hsp22, Hsp27, or αB-crystallin, suggesting that it might physically bring the chaperone families together into a complex. Indeed, addition of BAG3 coordinated the ability of Hsp22 and Hsp70 to refold denatured luciferase in vitro. Together, these results suggest that BAG3 physically and functionally links Hsp70 and sHsps.

Published
2017

36. Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma

Author

Lim, Jing Quan, Huang, Dachuan, Tang, Tiffany, Tan, Daryl, Laurensia, Yurike, Peng, Rou-Jun, Wong, Esther Kam Yin, Cheah, Daryl Ming Zhe, Chia, Burton Kuan Hui, Iqbal, Jabed, Grigoropoulos, Nicholas Francis, Nairismägi, Maarja-Liisa, Ng, Cedric Chuan Young, Rajasegaran, Vikneswari, Hong, Huangming, Kim, Seok Jin, Cho, Junhun, Tse, Eric, Mow, Benjamin, Cai, Qi-Chun, Poon, Li-Mei, Cai, Qing-qing, Tan, Jing, Chan, Jason Yongsheng, Lim, Johnathan Xiande, Goh, Yeow Tee, Phipps, Colin, Rötzschke, Olaf, Cheng, Chee Leong, Ha, Jeslin Chian Hung, Khoo, Lay Poh, Loh, Yvonne Su Ming, Au-Yeung, Rex, Chan, Thomas Sau-Yan, Kwong, Yok-Lam, Hwang, William, Kim, Won Seog, Bei, Jin-Xin, Lin, Tongyu, Ong, Choon Kiat, and Lim, Soon Thye

Published
2020
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37. Anticoagulation therapy patterns for acute treatment of venous thromboembolism in GARFIELD‐VTE patients

Author

Haas, Sylvia, Ageno, Walter, Weitz, Jeffrey I., Goldhaber, Samuel Z., Turpie, Alexander G.G., Goto, Shinya, Angchaisuksiri, Pantep, Dalsgaard Nielsen, Joern, Kayani, Gloria, Zaghdoun, Audrey, Farjat, Alfredo E., Schellong, Sebastian, Bounameaux, Henri, Mantovani, Lorenzo G., Prandoni, Paolo, Kakkar, Ajay K., Loualidi, Ab, Colak, Abdurrahim, Bezuidenhout, Abraham, Abdool‐Carrim, Abu, Azeddine, Addala, Beyers, Adriaan, Dees, Adriaan, Mohamed, Ahmed, Aksoy, Ahmet, Abiko, Akihiko, Watanabe, Akinori, Krichell, Alan, Fernandez, Alberto Alfredo, Tosetto, Alberto, Khotuntsov, Alexey, Oropallo, Alisha, Slocombe, Alison, Kelly, Allan, Clark, Amanda, Gad, Amr, Arouni, Amy, Schmidt, Andor, Berni, Andrea, Kleiban, Andres Javier, Machowski, Andrew, Kazakov, Andrey, Galvez, Angel, Lockman, Ann, Falanga, Anna, Chauhan, Anoop, Riera‐Mestre, Antoni, Mazzone, Antonino, D'Angelo, Armando, Herdy, Artur, Kato, Atsushi, Ebrahim, Ayman Abd Elhamid, Salem, Mahmoud, Husin, Azlan, Erdelyi, Barbara, Jacobson, Barry, Amann‐Vesti, Beatrice, Battaloglu, Bektas, Wilson, Benedicte, Cosmi, Benilde, Francois, Bergmann Jean, Toufek, Berremeli, Hunt, Beverley, Natha, Bhavesh, Mustafa, Bisher, Kho, Bonnie Chi Shan, Carine, Boulon, Zidel, Brian, Dominique, Brisot, Christophe, Brousse, Trimarco, Bruno, Luo, Canhua, Alberto Cuneo, Carlos, Sanchez Diaz, Carlos Jerjes, Schwencke, Carsten, Cader, Cas, Yavuz, Celal, Javier Zaidman, Cesar, Lunn, Charles, Wu, Chau‐Chung, Toh, Cheng Hock, Chiang, Chern‐En, Elisa, Chevrier, Hsia, Chien‐Hsun, Huang, Chien‐Lung, Kwok, Chi‐Hang Kevin, Wu, Chih‐Cheng, Huang, Chi‐Hung, Ward, Chris, Opitz, Christian, Jeanneret‐Gris, Christina, Ha, Chung Yin, Huang, Chun‐Yao, Bidi, Claude Luyeye, Smith, Clifford, Brauer, Cornelia, Lodigiani, Corrado, Francis, Couturaud, Wu, Cynthia, Staub, Daniel, Theodoro, Daniel, Poli, Daniela, Acevedo, Riesco, Adler, David, Jimenez, David, Keeling, David, Scott, David, Imberti, Davide, Creagh, Desmond, Helene, Desmurs‐Clavel, Hagemann, Dirk, Le Roux, Dirk, Skowasch, Dirk, Belenky, Dmitry, Dorokhov, Dmitry, Petrov, Dmitry, Zateyshchikov, Dmitry, Prisco, Domenico, Møller, Dorthe, Kucera, Dusan, Esheiba, Ehab M., Panchenko, Elizaveta, Dominique, Elkouri, Dogan, Emre, Kubat, Emre, Diaz Diaz, Enrique, Tse, Eric Wai Choi, Yeo, Erik, Hashas, Erman, Grochenig, Ernst, Tiraferri, Eros, Blessing, Erwin, Michèle, Escande Orthlieb, Usandizaga, Esther, Porreca, Ettore, Ferroni, Fabian, Nicolas, Falvo, Ayala‐Paredes, Félix, Koura, Firas, Henry, Fitjerald, Cosmi, Franco, Erdkamp, Frans, Kamalov, Gadel, Dalmau, Garcia‐Bragado, Damien, Garrigues, Klein, Garry, Shah, Gaurand, Hollanders, Geert, Merli, Geno, Plassmann, Georg, Platt, George, Poirier, Germain, Sokurenko, German, Haddad, Ghassan, Ali, Gholam, Agnelli, Giancarlo, Gan, Gin Gin, Kaye‐Eddie, Grace, Le Gal, Gregoire, Allen, Gregory, Llamas Esperón, Guillermo Antonio, Jean‐Paul, Guillot, Gerofke, Hagen, Elali, Hallah, Burianova, Hana, Ohler, Hans‐Juergen, Wang, Haofu, Darius, Harald, Gogia, Harinder S., Striekwold, Harry, Gibbs, Harry, Hasanoglu, Hatice, Turker, Hatice, Franow, Hendrik, De Raedt, Herbert, Schroe, Herman, ElDin, Hesham Salah, Zidan, Hesham, Nakamura, Hiroaki, Kim, Ho Young, Lawall, Holger, Zhu, Hong, Tian, Hongyan, Yhim, Ho‐Young, ten Cate, Hugo, Hwang, Hun Gyu, Shim, Hyeok, Kim, Igor, Libov, Igor, Sonkin, Igor, Suchkov, Igor, Song, Ik‐Chan, Kiris, Ilker, Staroverov, Ilya, Looi, Irene, De La Azuela Tenorio, Isabel M, Savas, Ismail, Gordeev, Ivan, Podpera, Ivo, Lee, Jae Hoon, Sathar, Jameela, Welker, James, Beyer‐Westendorf, Jan, Kvasnicka, Jan, Vanwelden, Jan, Kim, JangYong, Svobodova, Jaromira, Gujral, Jaspal, Marino, Javier, Galvar, Javier Tristan, Kassis, Jeannine, Kuo, Jen‐Yuan, Shih, Jhih‐Yuan, Kwon, JiHyun, Joh, Jin Hyun, Park, Jin Hyun, Kim, Jin Seok, Yang, Jinghua, Krupicka, Jiri, Lastuvka, Jiri, Pumprla, Jiri, Vesely, Jiri, Carlos Souto, Joan, Antônio Correa, João, Duchateau, Johan, Fletcher, John Perry, del Toro, Jorge, Chavez Paez, Jorge Guillermo, Araujo Filho, Jose Dalmo, Saraiva, Jose, Diaz Peromingo, Jose Antonio, Gomez Lara, Jose, Luis Fedele, Jose, Maria Surinach, Jose, Chacko, Joseph, Antonio Muntaner, Juan, Álvarez Benitez, Juan Carlos, Hoyos Abril, Juan Moreno, Humphrey, Julian, Bono, Julio, Kanda, Junji, Boondumrongsagoon, Juree, Yiu, Kai Hang, Chansung, Kanchana, Boomars, Karin, Burbury, Kate, Kondo, Katsuhiro, Karaarslan, Kemal, Takeuchi, Kensuke, Kroeger, Knut, Zrazhevskiy, Konstantin, Svatopluk, Koscál, Shyu, Kou‐Gi, Vandenbosch, Kristel, Chang, Kuan‐Cheng, Chiu, Kuan‐Ming, Jean‐Manuel, Kubina, Wern, Kwan Jing, Ueng, Kwo‐Chang, Norasetthada, Lalita, Binet, Laure, Chew, Lee Ping, Zhang, Lei, Cristina, Leone Maria, Tick, Lidwine, Beatriz Schiavi, Lilia, Wong, Lily Lee Lee, Borges, Lohana, Botha, Louis, Capiau, Luc, Timmermans, Luc, Eduardo López, Luciano, Ria, Luigi, Hernandez Blasco, Luis Manuel, Guzman, Luis Alberto, Flota Cervera, Luis, Isabelle, Mahe, Monreal Bosch, Manuel, de los Rios Ibarra, Manuel, Núñez Fernandez, Manuel, Carrier, Marc, Raul Barrionuevo, Marcelo, Alcocer Gamba, Marco Antonio, Cattaneo, Marco, Moia, Marco, Bowers, Margaret, Chetanachan, Mariam, Berli, Mario Alberto, Fixley, Mark, Faghih, Markus, Stuecker, Markus, Schul, Marlin, Banyai, Martin, Koretzky, Martin, Myriam, Martin, Gaffney, Mary Elizabeth, Hirano, Masao, Kanemoto, Masashi, Nakamura, Mashio, Tahar, Mersel, Emmanuel, Messas, Kovacs, Michael, Leahy, Michael, Levy, Michael, Munch, Michael, Olsen, Michael, De Pauw, Michel, Gustin, Michel, Van Betsbrugge, Michiel, Boyarkin, Mikhail, Homza, Miroslav, Koto, Modise, Abdool‐Gaffar, Mohamed, Nagib, Mohamed Ayman Fakhry, El‐Dessoki, Mohamed, Khan, Mohamed, Mohamed, Monniaty, Kim, Moo Hyun, Lee, Moon‐Hee, Soliman, Mosaad, Ahmed, Mostafa Shawky, el Bary, Mostafa Soliman Abd, Moustafa, Moustafa A., Hameed, Muhammad, Kanko, Muhip, Majumder, Mujibur, Zubareva, Nadezhda, Mumoli, Nicola, Abdullah, Nik Azim Nik, Makruasi, Nisa, Paruk, Nishen, Kanitsap, Nonglak, Duda, Norberto, Nordin, Nordiana, Nyvad, Ole, Barbarash, Olga, Gurbuz, Orcun, Vilamajo, Oscar Gomez, Nandayapa Flores, Oscar, Gur, Ozcan, Oto, Oztekin, Javier Marchena, Pablo, Carroll, Patrick, Lang, Pavel, MacCallum, Peter, von Bilderling, Peter Baron, Blombery, Peter, Verhamme, Peter, Jansky, Petr, Bernadette, Peuch, De Vleeschauwer, Philippe, Hainaut, Philippe, Ferrini, Piera Maria, Iamsai, Piriyaporn, Christian, Ponchaux, Viboonjuntra, Pongtep, Rojnuckarin, Ponlapat, Ho, Prahlad, Mutirangura, Pramook, Wells, Rachel, Martinez, Rafael, Miranda, Raimundo Tirado, Kroening, Ralf, Ratsela, Rapule, Reyes, Raquel Lopez, Diaz de Leon, Raul Franco, Wong, Raymond Siu Ming, Alikhan, Raz, Jerwan‐Keim, Reinhold, Otero, Remedios, Murena‐Schmidt, Renate, Canevascini, Reto, Ferkl, Richard, White, Richard, Van Herreweghe, Rika, Santoro, Rita, Klamroth, Robert, Mendes, Robert, Prosecky, Robert, Cappelli, Roberto, Spacek, Rudolf, Singh, Rupesh, Griffin, Sam, Na, Sang Hoon, Chunilal, Sanjeev, Middeldorp, Saskia, Nakazawa, Satoshi, Toh, See Guan, Christophe, Seinturier, Isbir, Selim, Raymundo, Selma, Ting, Seng Kiat, Motte, Serge, Aktogu, Serir Ozkan, Donders, Servaas, Cha, Seung Ick, Nam, Seung‐Hyun, Marie‐Antoinette, Sevestre‐Pietri, Maasdorp, Shaun, Sun, Shenghua, Wang, Shenming, Essameldin, Sherif Mohamed, Sholkamy, Sherif Mohamed, Kuki, Shintaro, Yoshida, Shuichi, Matsuoka, Shunzo, McRae, Simon, Watt, Simon, Patanasing, Siriwimon, Jean‐Léopold, Siwe‐Nana, Wongkhantee, Somchai, Bang, Soo‐Mee, Testa, Sophie, Zemek, Stanislav, Behrens, Steffen, Dominique, Stephan, Mellor, Stuart, Singh, Suaran Singh Gurcharan, Datta, Sudip, Chayangsu, Sunee, Solymoss, Susan, Everington, Tamara, Abdel‐Azim, Tarek Ahmed Adel, Suwanban, Tawatchai, Adademir, Taylan, Hart, Terence, Béatrice, Terriat, Luvhengo, Thifhelimbilu, Horacek, Thomas, Zeller, Thomas, Boussy, Tim, Reynolds, Tim, Biss, Tina, Chao, Ting‐Hsing, Casabella, Tomas Smith, Onodera, Tomoya, Numbenjapon, Tontanai, Gerdes, Victor, Cech, Vladimir, Krasavin, Vladimir, Tolstikhin, Vladimir, Bax, W.A., Malek, Wagih Fawzy Abdel, Ho, Wai Khoon, Pharr, Walter, Jiang, Weihong, Lin, Wei‐Hsiang, Zhang, Weihua, Tseng, Wei‐Kung, Lai, Wen‐Ter, De Backer, Wilfried, Haverkamp, Wilhelm, Yoshida, Winston, Korte, Wolfgang, Choi, Won II, Kim, Yang‐Ki, Tanabe, Yasuhiro, Ohnuma, Yasushi, Mun, Yeung‐Chul, Balthazar, Yohan, Park, Yong, Shibata, Yoshisato, Burov, Yuriy, Subbotin, Yuriy, Coufal, Zdenek, Yang, Zhenwen, Jing, Zhicheng, and Yang, Zhongqi

Published
2019
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38. Mitochondrial peroxiredoxin functions as crucial chaperone reservoir in Leishmania infantum

Author

Teixeira, Filipa, Castro, Helena, Cruz, Tânia, Tse, Eric, Koldewey, Philipp, Southworth, Daniel R, Tomás, Ana M, and Jakob, Ursula

Subjects
Biochemistry and Cell Biology, Biological Sciences, Vector-Borne Diseases, Emerging Infectious Diseases, Infectious Diseases, Infection, Good Health and Well Being, Animals, Leishmania infantum, Luciferases, Molecular Chaperones, Peroxiredoxins, Protein Folding, Virulence, chaperone, Leishmania, peroxiredoxin
Abstract

Cytosolic eukaryotic 2-Cys-peroxiredoxins have been widely reported to act as dual-function proteins, either detoxifying reactive oxygen species or acting as chaperones to prevent protein aggregation. Several stimuli, including peroxide-mediated sulfinic acid formation at the active site cysteine, have been proposed to trigger the chaperone activity. However, the mechanism underlying this activation and the extent to which the chaperone function is crucial under physiological conditions in vivo remained unknown. Here we demonstrate that in the vector-borne protozoan parasite Leishmania infantum, mitochondrial peroxiredoxin (Prx) exerts intrinsic ATP-independent chaperone activity, protecting a wide variety of different proteins against heat stress-mediated unfolding in vitro and in vivo. Activation of the chaperone function appears to be induced by temperature-mediated restructuring of the reduced decamers, promoting binding of unfolding client proteins in the center of Prx's ringlike structure. Client proteins are maintained in a folding-competent conformation until restoration of nonstress conditions, upon which they are released and transferred to ATP-dependent chaperones for refolding. Interference with client binding impairs parasite infectivity, providing compelling evidence for the in vivo importance of Prx's chaperone function. Our results suggest that reduced Prx provides a mitochondrial chaperone reservoir, which allows L. infantum to deal successfully with protein unfolding conditions during the transition from insect to the mammalian hosts and to generate viable parasites capable of perpetuating infection.

Published
2015

40. The Molecular Chaperone Hsp70 Activates Protein Phosphatase 5 (PP5) by Binding the Tetratricopeptide Repeat (TPR) Domain*

Author

Connarn, Jamie N, Assimon, Victoria A, Reed, Rebecca A, Tse, Eric, Southworth, Daniel R, Zuiderweg, Erik RP, Gestwicki, Jason E, and Sun, Duxin

Subjects
Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Enzyme Activation, Glycoproteins, HEK293 Cells, HSC70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Humans, Luciferases, Models, Chemical, Molecular Chaperones, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Tertiary, Signal Transduction, Hsp90, NMR, Peptides, Protein Phosphatase, Protein-protein Interactions, Cancer Signaling, Co-chaperones, Heat Shock Protein 70, Split Luciferase, Tethered Binding, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology
Abstract

Protein phosphatase 5 (PP5) is auto-inhibited by intramolecular interactions with its tetratricopeptide repeat (TPR) domain. Hsp90 has been shown to bind PP5 to activate its phosphatase activity. However, the functional implications of binding Hsp70 to PP5 are not yet clear. In this study, we find that both Hsp90 and Hsp70 bind to PP5 using a luciferase fragment complementation assay. A fluorescence polarization assay shows that Hsp90 (MEEVD motif) binds to the TPR domain of PP5 almost 3-fold higher affinity than Hsp70 (IEEVD motif). However, Hsp70 binding to PP5 stimulates higher phosphatase activity of PP5 than the binding of Hsp90. We find that PP5 forms a stable 1:1 complex with Hsp70, but the interaction appears asymmetric with Hsp90, with one PP5 binding the dimer. Solution NMR studies reveal that Hsc70 and PP5 proteins are dynamically independent in complex, tethered by a disordered region that connects the Hsc70 core and the IEEVD-TPR contact area. This tethered binding is expected to allow PP5 to carry out multi-site dephosphorylation of Hsp70-bound clients with a range of sizes and shapes. Together, these results demonstrate that Hsp70 recruits PP5 and activates its phosphatase activity which suggests dual roles for PP5 that might link chaperone systems with signaling pathways in cancer and development.

Published
2014

41. S149: OTHER MALIGNANCIES IN THE HISTORY OF CLL: THE FINAL ANALYSIS OF THE INTERNATIONAL MULTICENTER STUDY CONDUCTED BY ERIC, IN HARMONY.

Author

Chatzikonstantinou, Thomas, primary, Scarfò, Lydia, additional, Karakatsoulis, Georgios, additional, Minga, Eva, additional, Chamou, Dimitra, additional, Iacoboni, Gloria, additional, Kotaskova, Jana, additional, Demosthenous, Christos, additional, Alcoceba, Miguel, additional, Al-Shemari, Salem, additional, Aurran-Schleinitz, Thérèse, additional, Bacchiarri, Francesca, additional, Bellido, Mar, additional, Bijou, Fontanet, additional, Calleja, Anne, additional, Medina, Angeles, additional, Khan, Mehreen Ali, additional, Cassin, Ramona, additional, Chatzileontiadou, Sofia, additional, Collado, Rosa, additional, Davis, Zadie, additional, Dimou, Maria, additional, Donaldson, David, additional, Santos, Gimena Dos, additional, Dreta, Barbara, additional, Efstathopoulou, Maria, additional, El-Ashwah, Shaimaa, additional, Enrico, Alicia, additional, Fresa, Alberto, additional, Galimberti, Sara, additional, Galitzia, Andrea, additional, García-Serra, Rocío, additional, Gimeno, Eva, additional, González-Gascón-Y-Marín, Isabel, additional, Gozzetti, Alessandro, additional, Guarente, Valerio, additional, Guieze, Romain, additional, Gogia, Ajay, additional, Gupta, Ritu, additional, Harrop, Sean, additional, Hatzimichael, Eleftheria, additional, Herishanu, Yair, additional, Hernández-Rivas, José-Ángel, additional, Inchiappa, Luca, additional, Jaksic, Ozren, additional, Janssen, Susanne, additional, Kalicińska, Elżbieta, additional, Kamel, Laribi, additional, Karakus, Volkan, additional, Kater, Arnon P, additional, Kho, Bonnie, additional, Kislova, Maria, additional, Konstantinou, Εliana, additional, Koren-Michowitz, Maya, additional, Kotsianidis, Ioannis, additional, Kreitman, Robert J, additional, Labrador, Jorge, additional, Lad, Deepesh, additional, Levin, Mark-David, additional, Levy, Ilana, additional, Longval, Thomas, additional, Lopez-Garcia, Alberto, additional, Marquet, Juan, additional, Maynadié, Marc, additional, Maslejova, Stanislava, additional, Mayor-Bastida, Carlota, additional, Mihaljevic, Biljana, additional, Milosevic, Ivana, additional, Miras, Fatima, additional, Moia, Riccardo, additional, Morawska, Marta, additional, Murru, Roberta, additional, Nath, Uttam Kumar, additional, Navarro-Bailón, Almudena, additional, Oliveira, Ana C., additional, Olivieri, Jacopo, additional, Oscier, David, additional, Panovska-Stavridis, Irina, additional, Papaioannou, Maria, additional, Papajík, Tomas, additional, Phumphukhieo, Punyarat, additional, Pierie, Cheyenne, additional, Puiggros, Anna, additional, Rani, Lata, additional, Reda, Gianluigi, additional, Rigolin, Gian Matteo, additional, Ronson, Aharon, additional, Ruchlemer, Rosa, additional, de Deus Santos, Marcos Daniel, additional, Schipani, Mattia, additional, Schiwitza, Annett, additional, Shen, Yandong, additional, Simkovic, Martin, additional, Smirnova, Svetlana, additional, Sameh Abdelrahman Soliman, Dina, additional, Spacek, Martin, additional, Tadmor, Tamar, additional, Tomic, Kristina, additional, Tse, Eric, additional, Vassilakopoulos, Theodoros, additional, Visentin, Andrea, additional, Vitale, Candida, additional, Tresckow, Julia von, additional, Vrachiolias, George, additional, Vukovic, Vojin, additional, Walewska, Renata, additional, Wasik-Szczepanek, Ewa, additional, Xu, Zhenshu, additional, Yagci, Munci, additional, Yañez, Lucrecia, additional, Yassin, Mohamed, additional, Zuchnicka, Jana, additional, Angelopoulou, Maria, additional, Antic, Darko, additional, Biderman, Bella, additional, Catherwood, Mark, additional, Claus, Rainer, additional, Coscia, Marta, additional, Cuneo, Antonio, additional, Demirkan, Fatih, additional, Espinet, Blanca, additional, Gaidano, Gianluca, additional, Kalashnikova, Olga, additional, Laurenti, Luca, additional, Nikitin, Eugene, additional, Pangalis, Gerassimos A., additional, Panagiotidis, Panagiotis, additional, Mulligan, Stephen, additional, Popov, Viola Maria, additional, Pospisilova, Sarka, additional, Smolej, Lukas, additional, Sportoletti, Paolo, additional, Stavroyianni, Niki, additional, Tam, Constantine, additional, Trentin, Livio, additional, Chatzidimitriou, Anastasia, additional, Bosch, Francesc, additional, Doubek, Michael, additional, Ghia, Paolo, additional, and Stamatopoulos, Kostas, additional

Published
2023
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42. 36-month clinical outcomes of patients with venous thromboembolism: GARFIELD-VTE

Author

Turpie, Alexander G.G., primary, Farjat, Alfredo E., additional, Haas, Sylvia, additional, Ageno, Walter, additional, Weitz, Jeffrey I., additional, Goldhaber, Samuel Z., additional, Goto, Shinya, additional, Angchaisuksiri, Pantep, additional, Kayani, Gloria, additional, Lopes, Renato D., additional, Chiang, Chern-En, additional, Gibbs, Harry, additional, Tse, Eric, additional, Verhamme, Peter, additional, ten Cate, Hugo, additional, Muntaner, Juan, additional, Schellong, Sebastian, additional, Bounameaux, Henri, additional, Prandoni, Paolo, additional, Maheshwari, Uma, additional, Kakkar, Ajay K., additional, Loualidi, Ab, additional, Colak, Abdurrahim, additional, Bezuidenhout, Abraham, additional, Abdool-Carrim, Abu, additional, Azeddine, Addala, additional, Beyers, Adriaan, additional, Dees, Adriaan, additional, Mohamed, Ahmed, additional, Aksoy, Ahmet, additional, Abiko, Akihiko, additional, Watanabe, Akinori, additional, Krichell, Alan, additional, Fernandez, Alberto Alfredo, additional, Tosetto, Alberto, additional, Khotuntsov, Alexey, additional, Oropallo, Alisha, additional, Slocombe, Alison, additional, Kelly, Allan, additional, Clark, Amanda, additional, Gad, Amr, additional, Arouni, Amy, additional, Schmidt, Andor, additional, Berni, Andrea, additional, Kleiban, Andres Javier, additional, Machowski, Andrew, additional, Kazakov, Andrey, additional, Galvez, Angel, additional, Lockman, Ann, additional, Falanga, Anna, additional, Chauhan, Anoop, additional, Riera-Mestre, Antoni, additional, Mazzone, Antonino, additional, D'Angelo, Armando, additional, Herdy, Artur, additional, Kato, Atsushi, additional, Salem, Ayman Abd Elhamid Ebrahim Mahmoud, additional, Husin, Azlan, additional, Erdelyi, Barbara, additional, Jacobson, Barry, additional, Amann-Vesti, Beatrice, additional, Battaloglu, Bektas, additional, Wilson, Benedicte, additional, Cosmi, Benilde, additional, Francois, Bergmann Jean, additional, Toufek, Berremeli, additional, Hunt, Beverley, additional, Natha, Bhavesh, additional, Mustafa, Bisher, additional, Kho, Bonnie Chi Shan, additional, Carine, Boulon, additional, Zidel, Brian, additional, Dominique, Brisot, additional, Christophe, Brousse, additional, Trimarco, Bruno, additional, Luo, Canhua, additional, Cuneo, Carlos Alberto, additional, Diaz, Carlos Jerjes Sanchez, additional, Schwencke, Carsten, additional, Cader, Cas, additional, Yavuz, Celal, additional, Zaidman, Cesar Javier, additional, Lunn, Charles, additional, Wu, Chau-Chung, additional, Toh, Cheng Hock, additional, Elisa, Chevrier, additional, Hsia, Chien-Hsun, additional, Huang, Chien-Lung, additional, Kwok, Chi-Hang Kevin, additional, Wu, Chih-Cheng, additional, Huang, Chi-Hung, additional, Ward, Chris, additional, Opitz, Christian, additional, Jeanneret-Gris, Christina, additional, Ha, Chung Yin, additional, Huang, Chun-Yao, additional, Bidi, Claude Luyeye, additional, Smith, Clifford, additional, Brauer, Cornelia, additional, Lodigiani, Corrado, additional, Francis, Couturaud, additional, Wu, Cynthia, additional, Staub, Daniel, additional, Theodoro, Daniel, additional, Poli, Daniela, additional, Acevedo, David - Riesco, additional, Adler, David, additional, Jimenez, David, additional, Keeling, David, additional, Scott, David, additional, Imberti, Davide, additional, Creagh, Desmond, additional, Helene, Desmurs-Clavel, additional, Hagemann, Dirk, additional, Le Roux, Dirk, additional, Skowasch, Dirk, additional, Belenky, Dmitry, additional, Dorokhov, Dmitry, additional, Petrov, Dmitry, additional, Zateyshchikov, Dmitry, additional, Prisco, Domenico, additional, Møller, Dorthe, additional, Kucera, Dusan, additional, Esheiba, Ehab M., additional, Panchenko, Elizaveta, additional, Dominique, Elkouri, additional, Dogan, Emre, additional, Kubat, Emre, additional, Diaz, Enrique Diaz, additional, Tse, Eric Wai Choi, additional, Yeo, Erik, additional, Hashas, Erman, additional, Grochenig, Ernst, additional, Tiraferri, Eros, additional, Blessing, Erwin, additional, Michèle, Escande Orthlieb, additional, Usandizaga, Esther, additional, Porreca, Ettore, additional, Ferroni, Fabian, additional, Nicolas, Falvo, additional, Ayala-Paredes, Félix, additional, Koura, Firas, additional, Henry, Fitjerald, additional, Cosmi, Franco, additional, Erdkamp, Frans, additional, Kamalov, Gadel, additional, Dalmau, Garcia-Bragado, additional, Damien, Garrigues, additional, Klein, Garry, additional, Shah, Gaurand, additional, Hollanders, Geert, additional, Merli, Geno, additional, Plassmann, Georg, additional, Platt, George, additional, Poirier, Germain, additional, Sokurenko, German, additional, Haddad, Ghassan, additional, Ali, Gholam, additional, Agnelli, Giancarlo, additional, Gan, Gin Gin, additional, Kaye-Eddie, Grace, additional, Le Gal, Gregoire, additional, Allen, Gregory, additional, Esperón, Guillermo Antonio Llamas, additional, Jean-Paul, Guillot, additional, Gerofke, Hagen, additional, Elali, Hallah, additional, Burianova, Hana, additional, Ohler, Hans-Juergen, additional, Wang, Haofu, additional, Darius, Harald, additional, Gogia, Harinder S., additional, Striekwold, Harry, additional, Hasanoglu, Hatice, additional, Turker, Hatice, additional, Franow, Hendrik, additional, De Raedt, Herbert, additional, Schroe, Herman, additional, ElDin, Hesham Salah, additional, Zidan, Hesham, additional, Nakamura, Hiroaki, additional, Kim, Ho Young, additional, Lawall, Holger, additional, Zhu, Hong, additional, Tian, Hongyan, additional, Yhim, Ho-Young, additional, Hwang, Hun Gyu, additional, Shim, Hyeok, additional, Kim, Igor, additional, Libov, Igor, additional, Sonkin, Igor, additional, Suchkov, Igor, additional, Song, Ik-Chan, additional, Kiris, Ilker, additional, Staroverov, Ilya, additional, Looi, Irene, additional, De La Azuela Tenorio, Isabel M., additional, Savas, Ismail, additional, Gordeev, Ivan, additional, Podpera, Ivo, additional, Lee, Jae Hoon, additional, Sathar, Jameela, additional, Welker, James, additional, Beyer-Westendorf, Jan, additional, Kvasnicka, Jan, additional, Vanwelden, Jan, additional, Kim, JangYong, additional, Svobodova, Jaromira, additional, Gujral, Jaspal, additional, Marino, Javier, additional, Galvar, Javier Tristan, additional, Kassis, Jeannine, additional, Kuo, Jen-Yuan, additional, Shih, Jhih-Yuan, additional, Kwon, JiHyun, additional, Joh, Jin Hyun, additional, Park, Jin Hyun, additional, Kim, Jin Seok, additional, Yang, Jinghua, additional, Krupicka, Jiri, additional, Lastuvka, Jiri, additional, Pumprla, Jiri, additional, Vesely, Jiri, additional, Souto, Joan Carlos, additional, Correa, João Antônio, additional, Duchateau, Johan, additional, Fletcher, John Perry, additional, del Toro, Jorge, additional, Paez, Jorge Guillermo Chavez, additional, Nielsen, Jørn, additional, Filho, Jose Dalmo Araujo, additional, Saraiva, Jose, additional, Peromingo, Jose Antonio Diaz, additional, Lara, Jose Gomez, additional, Fedele, Jose Luis, additional, Surinach, Jose Maria, additional, Chacko, Joseph, additional, Muntaner, Juan Antonio, additional, Benitez, Juan Carlos Álvarez, additional, Abril, Juan Moreno Hoyos, additional, Humphrey, Julian, additional, Bono, Julio, additional, Kanda, Junji, additional, Boondumrongsagoon, Juree, additional, Yiu, Kai Hang, additional, Chansung, Kanchana, additional, Boomars, Karin, additional, Burbury, Kate, additional, Kondo, Katsuhiro, additional, Karaarslan, Kemal, additional, Takeuchi, Kensuke, additional, Kroeger, Knut, additional, Zrazhevskiy, Konstantin, additional, Svatopluk, Koscál, additional, Shyu, Kou-Gi, additional, Vandenbosch, Kristel, additional, Chang, Kuan-Cheng, additional, Chiu, Kuan-Ming, additional, Jean-Manuel, Kubina, additional, Wern, Kwan Jing, additional, Ueng, Kwo-Chang, additional, Norasetthada, Lalita, additional, Binet, Laure, additional, Chew, Lee Ping, additional, Zhang, Lei, additional, Cristina, Leone Maria, additional, Tick, Lidwine, additional, Schiavi, Lilia Beatriz, additional, Wong, Lily Lee Lee, additional, Borges, Lohana, additional, Botha, Louis, additional, Capiau, Luc, additional, Timmermans, Luc, additional, López, Luciano Eduardo, additional, Ria, Luigi, additional, Blasco, Luis Manuel Hernandez, additional, Guzman, Luis Alberto, additional, Cervera, Luis Flota, additional, Isabelle, Mahe, additional, Bosch, Manuel Monreal, additional, de los Rios Ibarra, Manuel, additional, Fernandez, Manuel Núñez, additional, Carrier, Marc, additional, Barrionuevo, Marcelo Raul, additional, Gamba, Marco Antonio Alcocer, additional, Cattaneo, Marco, additional, Moia, Marco, additional, Bowers, Margaret, additional, Chetanachan, Mariam, additional, Berli, Mario Alberto, additional, Fixley, Mark, additional, Faghih, Markus, additional, Stuecker, Markus, additional, Schul, Marlin, additional, Banyai, Martin, additional, Koretzky, Martin, additional, Myriam, Martin, additional, Gaffney, Mary Elizabeth, additional, Hirano, Masao, additional, Kanemoto, Masashi, additional, Nakamura, Mashio, additional, Tahar, Mersel, additional, Emmanuel, Messas, additional, Kovacs, Michael, additional, Leahy, Michael, additional, Levy, Michael, additional, Munch, Michael, additional, Olsen, Michael, additional, De Pauw, Michel, additional, Gustin, Michel, additional, Van Betsbrugge, Michiel, additional, Boyarkin, Mikhail, additional, Homza, Miroslav, additional, Koto, Modise, additional, Abdool-Gaffar, Mohamed, additional, Nagib, Mohamed Ayman Fakhry, additional, El-Dessoki, Mohamed, additional, Khan, Mohamed, additional, Mohamed, Monniaty, additional, Kim, Moo Hyun, additional, Lee, Moon-Hee, additional, Soliman, Mosaad, additional, Ahmed, Mostafa Shawky, additional, el Bary, Mostafa Soliman Abd, additional, Moustafa, Moustafa A., additional, Hameed, Muhammad, additional, Kanko, Muhip, additional, Majumder, Mujibur, additional, Zubareva, Nadezhda, additional, Mumoli, Nicola, additional, Abdullah, Nik Azim Nik, additional, Makruasi, Nisa, additional, Paruk, Nishen, additional, Kanitsap, Nonglak, additional, Duda, Norberto, additional, Nordin, Nordiana, additional, Nyvad, Ole, additional, Barbarash, Olga, additional, Gurbuz, Orcun, additional, Vilamajo, Oscar Gomez, additional, Flores, Oscar Nandayapa, additional, Gur, Ozcan, additional, Oto, Oztekin, additional, Marchena, Pablo Javier, additional, Carroll, Patrick, additional, Lang, Pavel, additional, MacCallum, Peter, additional, von Bilderling, Peter Baron, additional, Blombery, Peter, additional, Jansky, Petr, additional, Bernadette, Peuch, additional, De Vleeschauwer, Philippe, additional, Hainaut, Philippe, additional, Ferrini, Piera Maria, additional, Iamsai, Piriyaporn, additional, Christian, Ponchaux, additional, Viboonjuntra, Pongtep, additional, Rojnuckarin, Ponlapat, additional, Ho, Prahlad, additional, Mutirangura, Pramook, additional, Wells, Rachel, additional, Martinez, Rafael, additional, Miranda, Raimundo Tirado, additional, Kroening, Ralf, additional, Ratsela, Rapule, additional, Reyes, Raquel Lopez, additional, de Leon, Raul Franco Diaz, additional, Wong, Raymond Siu Ming, additional, Alikhan, Raz, additional, Jerwan-Keim, Reinhold, additional, Otero, Remedios, additional, Murena-Schmidt, Renate, additional, Canevascini, Reto, additional, Ferkl, Richard, additional, White, Richard, additional, Van Herreweghe, Rika, additional, Santoro, Rita, additional, Klamroth, Robert, additional, Mendes, Robert, additional, Prosecky, Robert, additional, Cappelli, Roberto, additional, Spacek, Rudolf, additional, Singh, Rupesh, additional, Griffin, Sam, additional, Na, Sang Hoon, additional, Chunilal, Sanjeev, additional, Middeldorp, Saskia, additional, Nakazawa, Satoshi, additional, Toh, See Guan, additional, Christophe, Seinturier, additional, Isbir, Selim, additional, Raymundo, Selma, additional, Ting, Seng Kiat, additional, Motte, Serge, additional, Aktogu, Serir Ozkan, additional, Donders, Servaas, additional, Cha, Seung Ick, additional, Nam, Seung-Hyun, additional, Marie-Antoinette, Sevestre-Pietri, additional, Maasdorp, Shaun, additional, Sun, Shenghua, additional, Wang, Shenming, additional, Essameldin, Sherif Mohamed, additional, Sholkamy, Sherif Mohamed, additional, Kuki, Shintaro, additional, Yoshida, Shuichi, additional, Matsuoka, Shunzo, additional, McRae, Simon, additional, Watt, Simon, additional, Patanasing, Siriwimon, additional, Jean-Léopold, Siwe-Nana, additional, Wongkhantee, Somchai, additional, Bang, Soo-Mee, additional, Testa, Sophie, additional, Zemek, Stanislav, additional, Behrens, Steffen, additional, Dominique, Stephan, additional, Mellor, Stuart, additional, Singh, Suaran Singh Gurcharan, additional, Datta, Sudip, additional, Chayangsu, Sunee, additional, Solymoss, Susan, additional, Everington, Tamara, additional, Abdel-Azim, Tarek Ahmed Adel, additional, Suwanban, Tawatchai, additional, Adademir, Taylan, additional, Hart, Terence, additional, Béatrice, Terriat, additional, Luvhengo, Thifhelimbilu, additional, Horacek, Thomas, additional, Zeller, Thomas, additional, Boussy, Tim, additional, Reynolds, Tim, additional, Biss, Tina, additional, Chao, Ting-Hsing, additional, Casabella, Tomas Smith, additional, Onodera, Tomoya, additional, Numbenjapon, Tontanai, additional, Gerdes, Victor, additional, Cech, Vladimir, additional, Krasavin, Vladimir, additional, Tolstikhin, Vladimir, additional, Bax, W.A., additional, Malek, Wagih Fawzy Abdel, additional, Ho, Wai Khoon, additional, Pharr, Walter, additional, Jiang, Weihong, additional, Lin, Wei-Hsiang, additional, Zhang, Weihua, additional, Tseng, Wei-Kung, additional, Lai, Wen-Ter, additional, De Backer, Wilfried, additional, Haverkamp, Wilhelm, additional, Yoshida, Winston, additional, Korte, Wolfgang, additional, Choi, Won Il, additional, Kim, Yang-Ki, additional, Tanabe, Yasuhiro, additional, Ohnuma, Yasushi, additional, Mun, Yeung-Chul, additional, Balthazar, Yohan, additional, Park, Yong, additional, Shibata, Yoshisato, additional, Burov, Yuriy, additional, Subbotin, Yuriy, additional, Coufal, Zdenek, additional, Yang, Zhenwen, additional, Jing, Zhicheng, additional, and Yang, Zhongqi, additional

Published
2023
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45. Clinical Practice Recommendations on Indication and Timing of Hematopoietic Cell Transplantation in Mature T Cell and NK/T Cell Lymphomas: An International Collaborative Effort on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation

Author

Kharfan-Dabaja, Mohamed A., Kumar, Ambuj, Ayala, Ernesto, Hamadani, Mehdi, Reimer, Peter, Gisselbrecht, Christian, d'Amore, Francesco, Jantunen, Esa, Ishida, Takashi, Bazarbachi, Ali, Foss, Francine, Advani, Ranjana, Fenske, Timothy S., Lazarus, Hillard M., Friedberg, Jonathan W., Aljurf, Mahmoud, Sokol, Lubomir, Tobinai, Kensei, Tse, Eric, Burns, Linda J., Chavez, Julio C., Reddy, Nishitha M., Suzuki, Ritsuro, Ahmed, Sairah, Nademanee, Auayporn, Mohty, Mohamad, Gopal, Ajay K., Fanale, Michelle A., Pro, Barbara, Moskowitz, Alison J., Sureda, Anna, Perales, Miguel Angel, Carpenter, Paul A., and Savani, Bipin N.

Published
2017
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46. IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patients

Author

Fiala, Milan, Chattopadhay, Madhuri, La Cava, Antonio, Tse, Eric, Liu, Guanghao, Lourenco, Elaine, Eskin, Ascia, Liu, Philip T, Magpantay, Larry, Tse, Stephen, Mahanian, Michelle, Weitzman, Rachel, Tong, Jason, Nguyen, Caroline, Cho, Tiffany, Koo, Patrick, Sayre, James, Martinez-Maza, Otoniel, Rosenthal, Mark J, and Wiedau-Pazos, Martina

Abstract

Abstract The contribution of inflammation to neurodegenerative diseases is increasingly recognized, but the role of inflammation in sporadic amyotrophic lateral sclerosis (sALS) is not well understood and no animal model is available. We used enzyme-linked immunosorbent assays (ELISAs) to measure the cytokine interleukin-17A (IL-17A) in the serum of ALS patients (n = 32; 28 sporadic ALS (sALS) and 4 familial ALS (fALS)) and control subjects (n = 14; 10 healthy subjects and 4 with autoimmune disorders). IL-17A serum concentrations were 5767 ± 2700 pg/ml (mean ± SEM) in sALS patients and 937 ± 927 pg/ml in fALS patients in comparison to 7 ± 2 pg/ml in control subjects without autoimmune disorders (p = 0.008 ALS patients vs. control subjects by Mann-Whitney test). Sixty-four percent of patients and no control subjects had IL-17A serum concentrations > 50 pg/ml (p = 0.003 ALS patients vs. healthy subjects by Fisher's exact test). The spinal cords of sALS (n = 8), but not control subjects (n = 4), were infiltrated by interleukin-1β- (IL-1β-), and tumor necrosis factor-α-positive macrophages (co-localizing with neurons), IL-17A-positive CD8 cells, and IL-17A-positive mast cells. Mononuclear cells treated with aggregated forms of wild type superoxide dismutase-1 (SOD-1) showed induction of the cytokines IL-1β, interleukin-6 (IL-6), and interleukin-23 (IL-23) that may be responsible for induction of IL-17A. In a microarray analysis of 28,869 genes, stimulation of peripheral blood mononuclear cells by mutant superoxide dismutase-1 induced four-fold higher transcripts of interleukin-1α (IL-1α), IL-6, CCL20, matrix metallopeptidase 1, and tissue factor pathway inhibitor 2 in mononuclear cells of patients as compared to controls, whereas the anti-inflammatory cytokine interleukin-10 (IL-10) was increased in mononuclear cells of control subjects. Aggregated wild type SOD-1 in sALS neurons could induce in mononuclear cells the cytokines inducing chronic inflammation in sALS spinal cord, in particular IL-6 and IL-17A, damaging neurons. Immune modulation of chronic inflammation may be a new approach to sALS.

Published
2010

49. Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly

Author

Braxton, Julian R., Shao, Hao, Tse, Eric, Gestwicki, Jason E., and Southworth, Daniel R.

Abstract

The mitochondrial chaperonin, mitochondrial heat shock protein 60 (mtHsp60), promotes the folding of newly imported and transiently misfolded proteins in the mitochondrial matrix, assisted by its co-chaperone mtHsp10. Despite its essential role in mitochondrial proteostasis, structural insights into how this chaperonin progresses through its ATP-dependent client folding cycle are not clear. Here, we determined cryo-EM structures of a hyperstable disease-associated human mtHsp60 mutant, V72I. Client density is identified in three distinct states, revealing interactions with the mtHsp60 apical domains and C termini that coordinate client positioning in the folding chamber. We further identify an asymmetric arrangement of the apical domains in the ATP state, in which an alternating up/down configuration positions interaction surfaces for simultaneous recruitment of mtHsp10 and client retention. Client is then fully encapsulated in mtHsp60–10, revealing prominent contacts at two discrete sites that potentially support maturation. These results identify distinct roles for the apical domains in coordinating client capture and progression through the chaperone cycle, supporting a conserved mechanism of group I chaperonin function.

Published
2024
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50. Asia‐Pacific Leukemia Consortium: An innovative and collaborative initiative to improve care of leukemia and related diseases in the Asia‐Pacific region.

Author

Lao, Zhentang, Tse, Eric Wai Choi, Chuncharunee, Suporn, Kwong, Yok Lam, Wei, Andrew, Ko, Bor Sheng, Kim, Jin Seok, Ng, Soo Chin, Wang, Jianxiang, and Goh, Yeow Tee

Subjects
*CONSORTIA, *LEUKEMIA, *PATIENT advocacy, *MEDICAL registries, *DATABASES
Abstract

The burden of leukemia and related diseases is rapidly growing in Asia. Currently, there is a paucity of regional collaborative groups/initiatives that focus exclusively on the management of leukemia in the Asia‐Pacific (APAC) region. The Asia‐Pacific Leukemia Consortium (APLC) was established on the 8 September 2021 to understand the status quo, unmet needs, and ways to improve the management of leukemia and related diseases in the APAC region. The APLC working group set up a group of experts from various countries (Singapore, Malaysia, Thailand, Hong Kong, Japan, South Korea, Taiwan, China, and Australia) to discuss on the status of: (i) clinical trials; (ii) disease registry database; (iii) genetic and tissue repository; (iv) patient advocacy and care; and (v) disease prevention and education in the APAC region. Low levels of awareness about leukemia amongst the public, lack of financial support, and limited access to newly approved therapies were identified as barriers to the implementation of effective leukemia management in low‐ or mid‐income Asian countries. Patients often enroll in clinical trials to gain access to novel/approved therapies. The APLC group aims to address the growing threat of leukemia through a collaborative approach to advance disease prevention, research, clinical trials, and education. [ABSTRACT FROM AUTHOR]

Published
2023
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