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1. Use of pure recombinant human enzymes to assess the disease‐causing potential of missense mutations in urea cycle disorders, applied to N‐acetylglutamate synthase deficiency

Author

Gougeard, Nadine, primary, Sancho‐Vaello, Enea, additional, Fernández‐Murga, M. Leonor, additional, Martínez‐Sinisterra, Borja, additional, Loukili‐Hassani, Badr, additional, Häberle, Johannes, additional, Marco‐Marín, Clara, additional, and Rubio, Vicente, additional

Published
2024
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2. C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

Author

Gargantilla, Marta, primary, Francés, Clara, additional, Adhav, Anmol, additional, Forcada-Nadal, Alicia, additional, Martínez-Gualda, Belén, additional, Martí-Marí, Olaia, additional, López-Redondo, María Luisa, additional, Melero, Roberto, additional, Marco-Marín, Clara, additional, Gougeard, Nadine, additional, Espinosa, Carolina, additional, Rubio-del-Campo, Antonio, additional, Ruiz-Partida, Rafael, additional, Hernández-Sierra, María del Pilar, additional, Villamayor-Belinchón, Laura, additional, Bravo, Jerónimo, additional, Llacer, José-Luis, additional, Marina, Alberto, additional, Rubio, Vicente, additional, San-Félix, Ana, additional, Geller, Ron, additional, and Pérez-Pérez, María-Jesús, additional

Published
2023
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3. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author

European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.

Published
2022

4. New findings with the IBV decoy for cell entry inhibition of SARS-CoV-2, and unique structural data for soluble dimeric ACE2 bound to the viral S trimer

Author

Forcada-Nadal, Alicia, López-Redondo, Marisa, Franco, María Luisa, Francés-Gómez, Clara, Ruiz-Partida, Rafael, Marco-Marín, Clara, Zamora-Caballero, Sara, Rubio-Del-Campo, Antonio, Hernández-Sierra, María del Pilar, Gougeard, Nadine, Espinosa, Carolina, Adhav, Anmol, Villamayor-Belinchón, Laura, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Ramón-Maiques, Santiago, Vilar, Marçal, Rubio, Vicente, Geller, Ron, Marina, Alberto, Llácer, José Luis, Forcada-Nadal, Alicia, López-Redondo, Marisa, Franco, María Luisa, Francés-Gómez, Clara, Ruiz-Partida, Rafael, Marco-Marín, Clara, Zamora-Caballero, Sara, Rubio-Del-Campo, Antonio, Hernández-Sierra, María del Pilar, Gougeard, Nadine, Espinosa, Carolina, Adhav, Anmol, Villamayor-Belinchón, Laura, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Ramón-Maiques, Santiago, Vilar, Marçal, Rubio, Vicente, Geller, Ron, Marina, Alberto, and Llácer, José Luis

Abstract

[Background] The SARS-CoV-2 spike protein (S) mediates the interaction of the virus with cellular membrane receptor (angiotensin-converting enzyme 2, ACE2). In previous PTI meetings, we reported heterologous production in vitro of the ACE2 extracellular domains modified by site-directed mutagenesis to increase its affinity for the S protein, to enable it to be used as viral entry inhibitor (decoy) by competing with the membrane-bound cellular receptor. We now test the value of these decoys for: 1) binding to S variants that emerged during the evolution of the pandemic in viral lineages of concern; and 2) inhibiting experimental cellular infection by pseudotyped virus expressing these S variants. Cellular syncytia formation has been described in several organs as a manifestation of severe COVID-19, and likely has pathogenic impact. To test further our decoys’ effectiveness, we studied their impact on cellular syncytia formation within an experimental in vitro cell culture model. Searching for effective decoys, we produced monomeric and dimeric ACE2 proteins, depending on the respective absence/presence of the extracellular collectrin domain. Interestingly, there are no reported structures of dimeric soluble ACE2 bound to the S protein. After extensive knowledge-guided trial-and-error, we succeeded in visualizing by cryo-electron microscopy (cryoEM) this interaction (~7-Å-resolution), and in understanding the challenges inherent in determining such a complex structural organization., [Methods] 1) Recombinant production and purification of the monomeric or dimeric ACE2, their decoys the receptor binding domain (RBD) and the S protein variants of interest. We used baculovirus/insect cells to produce ACE2s and RBDs, and human Expi293F cells for the S proteins. 2) Biolayer interferometry for assessing protein-protein interactions; 3) Use of a model system for monitoring viral cellular infection and its inhibition by decoys. We used a pseudotyped engineered vesicular stomatitis virus expressing and exposing at its surface the desired S protein variant, to infect appropriate SARS-CoV-2-susceptible mammalian cells; 4) Single-particle cryoEM; 5) Syncytia formation testing using an engineered cultured cell system in which heterologous surface expression of the S protein in one cell type induces syncytium formation in other cells expressing membrane-bound ACE2., [Results] Our decoys proved highly effective in preventing cellular infection by pseudotyped virus expressing the S proteins of different SARS-CoV-2 variants of concern. Biophysical results have validated the maintained interaction between the decoy and the various S protein variants. When introduced into the cellular model system for syncytia formation, the decoys proved capable of decreasing such formation. Puzzlingly, the monomeric decoy was more effective than the dimeric one. The cryoEM images unveiled an ACE2 dimer configuration, where the subunits, resembling the previously reported monomer, were oriented at an angle of >60º, in which the vortex was the interlinked collectrin domains. Both catalytic domains engage with a single RBD of one subunit from different S trimers. The formation of a network at high stoichiometries of both components poses a challenge for structure determination by cryoEM., [Conclusions] Unlike therapeutic antibodies, which proved ineffective on variants not initially used for their production, our decoys should be effective in preventing infection by all widely widespread SARS-CoV-2 variants.

Published
2023

6. C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

Author

European Commission, Instituto de Salud Carlos III, Generalitat Valenciana, Marina, Alberto [0000-0002-1334-5273], Llácer, José Luis [0000-0001-5304-1795], Rubio, Vicente [0000-0001-8124-1196], Marco-Marín, Clara [0000-0002-8813-3515], Bravo, Jerónimo [0000-0001-6695-2846], Gargantilla, Marta, Francés-Gómez, Clara, Adhav, Anmol, Forcada-Nadal, Alicia, Martínez-Gualda, Belén, Martí-Marí, Olaia, López-Redondo, Marisa, Melero, Roberto, Marco-Marín, Clara, Gougeard, Nadine, Espinosa, Carolina, Rubio-Del-Campo, Antonio, Ruiz-Partida, Rafael, Hernández-Sierra, María del Pilar, Villamayor-Belinchón, Laura, Bravo, Jerónimo, Llácer, José Luis, Marina, Alberto, Rubio, Vicente, San-Félix, Ana, Geller, Ron, Peréz-Pérez, María-Jesús, European Commission, Instituto de Salud Carlos III, Generalitat Valenciana, Marina, Alberto [0000-0002-1334-5273], Llácer, José Luis [0000-0001-5304-1795], Rubio, Vicente [0000-0001-8124-1196], Marco-Marín, Clara [0000-0002-8813-3515], Bravo, Jerónimo [0000-0001-6695-2846], Gargantilla, Marta, Francés-Gómez, Clara, Adhav, Anmol, Forcada-Nadal, Alicia, Martínez-Gualda, Belén, Martí-Marí, Olaia, López-Redondo, Marisa, Melero, Roberto, Marco-Marín, Clara, Gougeard, Nadine, Espinosa, Carolina, Rubio-Del-Campo, Antonio, Ruiz-Partida, Rafael, Hernández-Sierra, María del Pilar, Villamayor-Belinchón, Laura, Bravo, Jerónimo, Llácer, José Luis, Marina, Alberto, Rubio, Vicente, San-Félix, Ana, Geller, Ron, and Peréz-Pérez, María-Jesús

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting enzyme (ACE2). To search for inhibitors of this key step in viral infection, we screened an in-house library of multivalent tryptophan derivatives. Using VSV-S pseudoparticles, we identified compound 2 as a potent entry inhibitor lacking cellular toxicity. Chemical optimization of 2 rendered compounds 63 and 65, which also potently inhibited genuine SARS-CoV-2 cell entry. Thermofluor and microscale thermophoresis studies revealed their binding to S and to its isolated receptor binding domain (RBD), interfering with the interaction with ACE2. High-resolution cryoelectron microscopy structure of S, free or bound to 2, shed light on cell entry inhibition mechanisms by these compounds. Overall, this work identifies and characterizes a new class of SARS-CoV-2 entry inhibitors with clear potential for preventing and/or fighting COVID-19.

Published
2023

7. Impact of small molecule-mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism

Author

Swiss National Science Foundation, Wolfermann-Naegeli Foundation, Research Council of Norway, Fundación Ramón Areces, European Research Council, Rubio, Vicente [0000-0001-8124-1196], Makris, Georgios, Kayhan, Semih, Kreuzer, Marvin, Rufenacht, Veronique, Faccin, Erica, Underhaug, Jarl, Díez-Fernández, Carmen, Knobel, Philip A., Poms, Martin, Gougeard, Nadine, Rubio, Vicente, Martínez, Aurora, Pruschy, Martin, Haberle, Johannes, Swiss National Science Foundation, Wolfermann-Naegeli Foundation, Research Council of Norway, Fundación Ramón Areces, European Research Council, Rubio, Vicente [0000-0001-8124-1196], Makris, Georgios, Kayhan, Semih, Kreuzer, Marvin, Rufenacht, Veronique, Faccin, Erica, Underhaug, Jarl, Díez-Fernández, Carmen, Knobel, Philip A., Poms, Martin, Gougeard, Nadine, Rubio, Vicente, Martínez, Aurora, Pruschy, Martin, and Haberle, Johannes

Published
2023

8. Impact of small molecule‐mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism

Author

Makris, Georgios; https://orcid.org/0000-0001-9097-1991, Kayhan, Semih; https://orcid.org/0000-0002-0328-7647, Kreuzer, Marvin, Rüfenacht, Véronique, Faccin, Erica; https://orcid.org/0000-0002-8817-4923, Underhaug, Jarl; https://orcid.org/0000-0003-0346-3986, Diez‐Fernandez, Carmen; https://orcid.org/0000-0002-2500-9373, Knobel, Philip A; https://orcid.org/0000-0003-1587-1530, Poms, Martin; https://orcid.org/0000-0002-4426-314X, Gougeard, Nadine; https://orcid.org/0000-0001-7338-7267, Rubio, Vicente; https://orcid.org/0000-0001-6099-5853, Martinez, Aurora; https://orcid.org/0000-0003-1643-6506, Pruschy, Martin; https://orcid.org/0000-0002-3124-9015, Häberle, Johannes; https://orcid.org/0000-0003-0635-091X, Makris, Georgios; https://orcid.org/0000-0001-9097-1991, Kayhan, Semih; https://orcid.org/0000-0002-0328-7647, Kreuzer, Marvin, Rüfenacht, Véronique, Faccin, Erica; https://orcid.org/0000-0002-8817-4923, Underhaug, Jarl; https://orcid.org/0000-0003-0346-3986, Diez‐Fernandez, Carmen; https://orcid.org/0000-0002-2500-9373, Knobel, Philip A; https://orcid.org/0000-0003-1587-1530, Poms, Martin; https://orcid.org/0000-0002-4426-314X, Gougeard, Nadine; https://orcid.org/0000-0001-7338-7267, Rubio, Vicente; https://orcid.org/0000-0001-6099-5853, Martinez, Aurora; https://orcid.org/0000-0003-1643-6506, Pruschy, Martin; https://orcid.org/0000-0002-3124-9015, and Häberle, Johannes; https://orcid.org/0000-0003-0635-091X

Abstract

Metabolically induced cancer heterogeneity creates a largesourceofnovelpotentialtargetstowardsanenhancedther-apeutic window alone and in combination with classicchemo-andradiotherapy[1,2 ].Thisisofparticularinterestfor non-small cell lung cancer (NSCLC), which accountsfor more than 80% of all lung tumor types characterizedby limited responses to current treatment options [3–5].Genetically-definedKRAS/LKB1-mutant NSCLC tumorsexploit the proximal urea cycle enzyme carbamoyl phos-phate synthetase 1 (CPS1) as an intermediate step forpyrimidine biosynthesis, thereby contrasting its crucialhepatic role in ammonia detoxification [6–8]. Thus, CPS1could serve as a novel target for NSCLC susceptibility(Figure1A). In this study, we investigated the metabolicchanges observed in both NSCLC and healthy hepaticsystems following the identification, characterization andapplication of a small molecule inhibitor of ectopic CPS1functionality.

Published
2023

9. Impact of small molecule‐mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism

Author

Makris, Georgios, primary, Kayhan, Semih, additional, Kreuzer, Marvin, additional, Rüfenacht, Véronique, additional, Faccin, Erica, additional, Underhaug, Jarl, additional, Diez‐Fernandez, Carmen, additional, Knobel, Philip A., additional, Poms, Martin, additional, Gougeard, Nadine, additional, Rubio, Vicente, additional, Martinez, Aurora, additional, Pruschy, Martin, additional, and Häberle, Johannes, additional

Published
2023
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10. Impact of small molecule‐mediated inhibition of ammonia detoxification on lung malignancies and liver metabolism

Author

Makris, Georgios, Kayhan, Semih, Kreuzer, Marvin, Rüfenacht, Véronique, Faccin, Erica, Underhaug, Jarl, Diez‐Fernandez, Carmen, Knobel, Philip A, Poms, Martin, Gougeard, Nadine, Rubio, Vicente, Martinez, Aurora, Pruschy, Martin, Häberle, Johannes, and University of Zurich

Subjects
Cancer Research, Oncology, 10036 Medical Clinic, 610 Medicine & health, 10044 Clinic for Radiation Oncology
Published
2023
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11. CryoEM structures of the SARS-CoV-2 spike bound to antivirals

Author

López-Redondo, María Luisa, Marco-Marín, Clara, Gougeard, Nadine, Forcada-Nadal, Alicia, Adhav, Anmol, Zamora-Caballero, Sara, Melero, Roberto, Hurtado, Ramón, Peréz-Pérez, María-Jesús, Bravo Sicilia, Jerónimo, Rubio, Vicente, Marina, Alberto, and Llacer Guerri, Jose Luis

Abstract

(Póster 63) Background: Single-particle cryoelectron microscopy (cryoEM) has played a key role in the fight against COVID-19. The molecular mechanisms for the action of some of the currently approved drugs targeting the SARS-CoV-2 RNA-dependent RNA polymerase, the fast developments of the current available vaccines and antibody therapies are examples of the impact of the knowledge gained from the cryoEM structures of SARS-CoV-2 proteins in complex with proteins (ACE2 or antibodies/nanobodies) or small compounds. Our aim is to use this technology to understand structurally how certain antiviral compounds and proteins targeting the spike may inhibit viral entry. Methods: 1) Production of wild-type and mutated spike and ACE2 proteins using baculovirus/insect cells. 2) Spike binding kinetics: protein-protein and protein-small compound interactions measured by BLI Biolayer interferometry (BLI) and/or microscale Thermophoresis (MST). 3) Buffer optimization for cryoEM grid preparation of spike variants by thermal shift assays and negative-staining electron microscopy (NSEM). These techniques are also used to adjust the molar ratio of spike:ACE2 and spike:small-compound complexes. 4) Structural characterization by cryoEM. Results: At IBV-CSIC we have created a pipeline for the production and characterization of several spike variants and ACE2 decoys. While this pipeline is described in detail in other oral/poster communications, this communication is centered around one of the pillars within this pipeline; the structural characterization of possible drug candidates bound to the SARS-CoV-2 spike by cryoEM. In this way, we have successfully solved structures of the spike bound to: A) protein inhibitors as ACE2 decoys; B) a small inhibitory compound; C) mixtures of proteins and small-compound (nanobody-heparan derivative) working cooperatively as inhibitors. These protein/drug candidates were previously selected based on the results obtained in our interactomics platform, whereas their concentration and the buffer conditions for cryoEM grids preparation were established based on thermal shift assays and NSEM. Conclusion: CryoEM is a powerful tool to directly visualize the effect caused by a potential drug on a protein target. In a short period of time we have developed this technique in our institute to be applied to the SARS-CoV-2 spike protein, not only to obtain high-resolution structures of SARS- CoV-2 spike variants of concern (see WP4) but also to obtain the structures of complexes of the spike with various inhibitory compounds of very different nature.

Published
2022

12. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation

Author

European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness.

Published
2021

13. Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus

Author

Becker, Yann L. C., primary, Gagné, Jean‐Philippe, additional, Julien, Anne‐Sophie, additional, Lévesque, Tania, additional, Allaeys, Isabelle, additional, Gougeard, Nadine, additional, Rubio, Vicente, additional, Boisvert, François‐Michel, additional, Jean, Dominique, additional, Wagner, Eric, additional, Poirier, Guy G., additional, Fortin, Paul R., additional, and Boilard, Éric, additional

Published
2022
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14. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

Author

Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis A., Montoliu, Lluís, Carracedo, Angel, Millán, José M., Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José Antonio, Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodríguez de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto, Sanz, Pascual, Rubio, Vicente, and Llácer, José L.

Subjects
Biomedical Research, Epidemiology, Novel genes, Research network, New therapeutic approaches, Rare diseases, Rare Diseases, Diagnòstic, Diagnosis, Genetics, Humans, Malalties rares, Epidemiologia, Genètica, Genetics (clinical)
Abstract

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A, CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research., This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation

Published
2022

15. Supplementary Information: The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Published
2022

16. The role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Published
2022

17. CryoEM structures of the SARS-CoV-2 spike bound to antivirals

Author

López-Redondo, Marisa, Marco-Marín, Clara, Gougeard, Nadine, Forcada-Nadal, Alicia, Adhav, Anmol, Zamora-Caballero, Sara, Melero, Roberto, Hurtado, Ramón, Peréz-Pérez, María-Jesús, Bravo Sicilia, Jerónimo, Rubio, Vicente, Marina, Alberto, Llacer Guerri, Jose Luis, López-Redondo, Marisa, Marco-Marín, Clara, Gougeard, Nadine, Forcada-Nadal, Alicia, Adhav, Anmol, Zamora-Caballero, Sara, Melero, Roberto, Hurtado, Ramón, Peréz-Pérez, María-Jesús, Bravo Sicilia, Jerónimo, Rubio, Vicente, Marina, Alberto, and Llacer Guerri, Jose Luis

Abstract

(Póster 63) Background: Single-particle cryoelectron microscopy (cryoEM) has played a key role in the fight against COVID-19. The molecular mechanisms for the action of some of the currently approved drugs targeting the SARS-CoV-2 RNA-dependent RNA polymerase, the fast developments of the current available vaccines and antibody therapies are examples of the impact of the knowledge gained from the cryoEM structures of SARS-CoV-2 proteins in complex with proteins (ACE2 or antibodies/nanobodies) or small compounds. Our aim is to use this technology to understand structurally how certain antiviral compounds and proteins targeting the spike may inhibit viral entry. Methods: 1) Production of wild-type and mutated spike and ACE2 proteins using baculovirus/insect cells. 2) Spike binding kinetics: protein-protein and protein-small compound interactions measured by BLI Biolayer interferometry (BLI) and/or microscale Thermophoresis (MST). 3) Buffer optimization for cryoEM grid preparation of spike variants by thermal shift assays and negative-staining electron microscopy (NSEM). These techniques are also used to adjust the molar ratio of spike:ACE2 and spike:small-compound complexes. 4) Structural characterization by cryoEM. Results: At IBV-CSIC we have created a pipeline for the production and characterization of several spike variants and ACE2 decoys. While this pipeline is described in detail in other oral/poster communications, this communication is centered around one of the pillars within this pipeline; the structural characterization of possible drug candidates bound to the SARS-CoV-2 spike by cryoEM. In this way, we have successfully solved structures of the spike bound to: A) protein inhibitors as ACE2 decoys; B) a small inhibitory compound; C) mixtures of proteins and small-compound (nanobody-heparan derivative) working cooperatively as inhibitors. These protein/drug candidates were previously selected based on the results obtained in our interactomics platform, wher

Published
2022

18. Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus

Author

Canadian Institutes of Health Research, Fonds de Recherche du Québec, Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, Rubio, Vicente [0000-0001-8124-1196], Becker, Yann L. C., Gagne, Jean-Philippe, Julien, Anne-Sophie, Levesque, Tania, Allaeys, Isabelle, Gougeard, Nadine, Rubio, Vicente, Boisvert, Francois-Michel, Jean, Dominique, Wagner, Eric, Poirier, Guy G., Fortin, Paul R., Boilard, Eric, Canadian Institutes of Health Research, Fonds de Recherche du Québec, Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, Rubio, Vicente [0000-0001-8124-1196], Becker, Yann L. C., Gagne, Jean-Philippe, Julien, Anne-Sophie, Levesque, Tania, Allaeys, Isabelle, Gougeard, Nadine, Rubio, Vicente, Boisvert, Francois-Michel, Jean, Dominique, Wagner, Eric, Poirier, Guy G., Fortin, Paul R., and Boilard, Eric

Abstract

Objective: Mitochondria are organelles that exhibit several bacterial features, such as a double-stranded genome with hypomethylated CpG islands, formylated proteins, and cardiolipin-containing membranes. In systemic lupus erythematosus (SLE), mitochondria and their inner components are released into the extracellular space, potentially eliciting a proinflammatory response from the immune system. While cardiolipin and mitochondrial DNA and RNA are confirmed targets of autoantibodies, other antigenic mitochondrial proteins in SLE remain to be identified. The present study was undertaken to characterize the protein repertoire recognized by antimitochondrial antibodies (AMAs) in patients with SLE. Methods: Using shotgun proteomic profiling, we identified 1,345 proteins, 431 of which were associated with the mitochondrial proteome. Immunoreactivities to several of these candidate proteins were assessed in serum samples from a local cohort (n = 30 healthy donors and 87 patients with SLE) using enzyme-linked immunosorbent assay, and further analyzed for associations with demographic and disease characteristics. Results: We determined that IgG antibodies to the complement component C1q binding protein were significantly elevated in the patients with SLE (P = 0.049) and were also associated with lupus anticoagulant positivity (P = 0.049). Elevated levels of IgG antibodies against mitochondrial protein mitofusin 1 (MFN-1) were promising predictors of SLE diagnosis in our cohort (adjusted odds ratio 2.99 [95% confidence interval 1.39-6.43], P = 0.0044). Moreover, increased levels of anti-MFN-1 were associated with the presence of antiphospholipids (P = 0.011) and anti-double-stranded DNA (P = 0.0005). Conclusion: In this study, we characterized the mitochondrial repertoire targeted by AMAs in the setting of SLE. Our results indicate that autoantibodies can recognize secreted and/or surface proteins of mitochondrial origin. Profiling of the AMA repertoire in large prospective

Published
2022

19. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

Author

Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], Llácer, José L. [0000-0001-5304-1795], Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis Alberto, Montoliu, Lluís, Carracedo, Ángel, Millán, José María, Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José A., Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodriguez-de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana Belén, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], Llácer, José L. [0000-0001-5304-1795], Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis Alberto, Montoliu, Lluís, Carracedo, Ángel, Millán, José María, Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José A., Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodriguez-de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana Belén, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., and Nieto, M. Ángela

Abstract

CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research.

Published
2022

20. Patología molecular y cristalografía de rayos X arrojan nueva luz sobre estructura-función de la carbamil fosfato sintetasa 1 humana (CPS1) (G01 35 P 027)

Author

Fundación Ramón Areces, Gougeard, Nadine, Díez-Fernández, Carmen, Cima, Sergio de, Polo, Luis Mariano, Marco-Marín, Clara, Fita, Ignacio, Rubio, Vicente, Fundación Ramón Areces, Gougeard, Nadine, Díez-Fernández, Carmen, Cima, Sergio de, Polo, Luis Mariano, Marco-Marín, Clara, Fita, Ignacio, and Rubio, Vicente

Abstract

(G01 35 P 027) La CPS1 es la entrada-interruptor del ciclo de la urea, operada por su activador esencial N-acetil-L-glutamato (NAG). Este ciclo es clave para la detoxificación del amonio derivado del catabolismo de las proteínas. Nuestras dos estructuras cristalinas de CPS1 humana sin ligandos o unidas a 2ADP, K+, Mg2+ y NAG, demostraron (De Cima et al. Sci Reports2015) su composición por 6 dominios globulares, dos de ellos catalíticos y homólogos, otro de activación por NAG y un cuarto de integración, quedando por determinar la función de sus dos dominios N-terminales (~400 aas.), reminiscentes de la subunidad menor de las CPSs anabólicas bacterianas. Hemos abordado la determinación de dicha función mediante mutagénesis dirigida, usando los datos genéticos de pacientes con déficit de CPS1 como atajo para elegir qué mutaciones introducir. En 30 mutantes humanos de estos dominios, producidos en y purificados de un sistema de baculovirus/células de insecto, hemos realizado ensayos de estabilidad, de actividad enzimática, y determinado las constantes cinéticas para los sustratos y el NAG. Los resultados indican un importante papel estabilizador de los dominios N-terminales, explicando su conservación en CPS1 a pesar de que han perdido la función ancestral glutaminasa de la subunidad menor de las CPSs bacterianas. Las estructuras ya determinadas, representativas de ambos extremos del proceso de activación de la CPS1, junto con una nueva estructura presentada aquí para una forma intermedia de activación pre-unión de NAG, fundamentan estructuralmente dicho papel estabilizador, a la vez que arrojan luz sobre el inicio del proceso de activación.

Published
2022

21. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

Author

Luque, Juan, Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, de Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis A., Montoliu, Lluís, Carracedo, Angel, Millan, Jose M., Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa M., Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José Antonio, Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero, Rosa, Jiménez-Estrada, Juan Andrés, Manguán García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona, Rosario, Rivera-Barahona, Ana, Rodríguez de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Heredia, Miguel, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], and Llácer, José L. [0000-0001-5304-1795]

Subjects
Novel genes, Genetics, Research network, New therapeutic approaches, Rare diseases
Abstract

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research. This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation

Published
2022

23. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

Author

Panza, Emanuele, Escamilla-Honrubia, Juan M., Marco-Marín, Clara, Gougeard, Nadine, De Michele, Giuseppe, Morra, Vincenzo Brescia, Liguori, Rocco, Salviati, Leonardo, Donati, Maria Alice, Cusano, Roberto, Pippucci, Tommaso, Ravazzolo, Roberto, Németh, Andrea H., Smithson, Sarah, Davies, Sally, Hurst, Jane A., Bordo, Domenico, Rubio, Vicente, and Seri, Marco

Published
2016
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24. Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine

Author

Martinelli, Diego, Häberle, Johannes, Rubio, Vicente, Giunta, Cecilia, Hausser, Ingrid, Carrozzo, Rosalba, Gougeard, Nadine, Marco-Marín, Clara, Goffredo, Bianca M., Meschini, Maria Chiara, Bevivino, Elsa, Boenzi, Sara, Colafati, Giovanna Stefania, Brancati, Francesco, Baumgartner, Matthias R., and Dionisi-Vici, Carlo

Published
2012
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25. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation.

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczór, Miłosz, Mata, Carlos P., Krieger, James, Ruiz-Rodriguez, Paula, López-Redondo, Maria Luisa, Francés-Gómez, Clara, Melero, Roberto, Sánchez-Sorzano, Carlos Óscar, Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jeronimo, Rubio, Vicente, and Marina, Alberto

Subjects
SARS-CoV-2, GENETIC mutation, VACCINE effectiveness, VIRAL mutation, VIRAL genomes, COVID-19, AVIAN influenza
Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness. Author summary: Since early 2020, the trajectory of the COVID-19 pandemic has mostly been shaped by the appearance of novel variants of the SARS-CoV-2 virus. Accordingly, much of the scientific effort has been directed toward the question of explaining, understanding, and predicting the evolutionary fate of individual mutations in the viral genome. In this article, we focus on A222V, a particular mutation in the Spike protein that emerged in Spain in mid-2020 and reappeared independently in the AY.4.2 subvariant of Delta one year later. As reemerging mutations often indicate an evolutionary advantage, we explored potential mechanisms linking A222V to biologically relevant outcomes. Using serological, functional, structural, and computational approaches, we identified key molecular-level differences conferred by A222V that potentially explain its repeated emergence in different genetic backgrounds. Our results point to subtle changes in the dynamic behavior of the receptor-binding domain in the binding-competent "up" conformation, ones that affect receptor binding itself, but can also act synergistically with other mutations by changing the accessibility of key residues involved in molecular recognition. [ABSTRACT FROM AUTHOR]

Published
2022
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26. N-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects

Author

Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Inocente Inocente, Rubio, Vicente[0000-0001-8124-1196], Yap, Sufin, Gougeard, Nadine, Hart, Anthony R., Barcelona, Belén, Rubio, Vicente, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Fundación Inocente Inocente, Rubio, Vicente[0000-0001-8124-1196], Yap, Sufin, Gougeard, Nadine, Hart, Anthony R., Barcelona, Belén, and Rubio, Vicente

Abstract

N-carbamoyl-l-glutamate (NCG), the N-acetyl-l-glutamate analogue used to treat N-acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG-responsiveness could be mutation-specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity (V max; ~2-fold reduction), and apparent affinity (~5-fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven.

Published
2019

28. Deciphering the mechanism by which 1-pyrrolin-5-carboxylate synthetase defects associate with dominant and recessive human pathologies

Author

Escamilla Honrubia, Juan Manuel, Marco-Marín, Clara, Gougeard, Nadine, Rubio, Vicente, and Ministerio de Economía y Competitividad (España)

Abstract

Póster original presentado al XXXVIII Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Valencia, 7-10 de septiembre de 2015, Δ1-Pyrrolin-5-carboxylate synthetase (P5CS) is a bifunctional enzyme that catalyzesthe first two steps of ornithine/proline biosynthesis in plants and animals. It is composed of an N-terminal glutamate-5-kinase (G5K) domain that uses ATP to phosphorylate the γ-carboxylate of glutamate, and of a C-terminal L-glutamyl-5-phosphate reductase (G5PR) domain that reductively dephosphorylates L-glutamyl-5-phosphate to L-glutamate-5-semialdehyde. This compound spontaneously cyclizes to Δ1-pyrrolin-5-carboxylate, thus being a precursor of both ornithine and proline. Human P5CS deficiency was associated with a fasting hyperammonemia syndrome with cataracts and vomiting. Then the syndrome was expanded to include a cutis laxa phenotype and more recently it has been associated with spastic paraplegia of dominant or recessive inheritance. Using our baculovirus/insect cell system for producing pure recombinant human P5CS, we introduced dominant and recessive mutations in the enzyme by site-directed mutagenesis, assaying enzyme activity. All the mutations, irrespectively of the type of inheritance they gave, inactivated the catalytic domain of P5CS where they mapped. Gel filtration and modelling evidence strongly suggests that the mutations giving dominant inheritance appear to cause their effects by a negative dominant mechanism. In particular, they are located on the surface of the two domains, in places that in E. coli G5K (a monofuntional tetrameric enzyme) are used in interactions with adjacent domains. Therefore, these dominant mutations may disturb the hexameric enzyme architecture, preventing potential "in vivo" channelling of L-glutamyl-5-phosphate from the G5K domain to a G5PR domain from an adjacent subunit., BFU2014-58229-P(MINECO).

Published
2015

30. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

Author

Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Rubio, Vicente [0000-0001-8124-1196], Escamilla-Honrubia, Juan Manuel [0000-0003-0154-6569], Panza, Emanuele, Escamilla-Honrubia, Juan Manuel, Marco-Marín, Clara, Gougeard, Nadine, De Michele, Giuseppe, Brescia Morra, Vincenzo, Liguori, Rocco, Salviati, Leonardo, Donati, Maria Alice, Cusano, Roberto, Pippucci, Tommaso, Ravazzolo, Roberto, Nemeth, Andrea H, Smithson, Sarah, Davies, Sally, Hurst, Jane A, Bordo, Domenico, Rubio, Vicente, Seri, Marco, Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Rubio, Vicente [0000-0001-8124-1196], Escamilla-Honrubia, Juan Manuel [0000-0003-0154-6569], Panza, Emanuele, Escamilla-Honrubia, Juan Manuel, Marco-Marín, Clara, Gougeard, Nadine, De Michele, Giuseppe, Brescia Morra, Vincenzo, Liguori, Rocco, Salviati, Leonardo, Donati, Maria Alice, Cusano, Roberto, Pippucci, Tommaso, Ravazzolo, Roberto, Nemeth, Andrea H, Smithson, Sarah, Davies, Sally, Hurst, Jane A, Bordo, Domenico, Rubio, Vicente, and Seri, Marco

Published
2016

31. Understanding N-Acetyl-L-Glutamate Synthase Deficiency: Mutational Spectrum, Impact of Clinical Mutations on Enzyme Functionality, and Structural Considerations

Author

Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Rubio, Vicente [0000-0001-8124-1196], Sancho-Vaello, Enea, Marco-Marín, Clara, Gougeard, Nadine, Fernández-Murga, María Leonor, Rufenacht, Veronique, Mustedanagic, Merima, Rubio, Vicente, Häberle, Johannes, Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Rubio, Vicente [0000-0001-8124-1196], Sancho-Vaello, Enea, Marco-Marín, Clara, Gougeard, Nadine, Fernández-Murga, María Leonor, Rufenacht, Veronique, Mustedanagic, Merima, Rubio, Vicente, and Häberle, Johannes

Abstract

N-acetyl-L-glutamate synthase (NAGS) deficiency (NAGSD), the rarest urea cycle defect, is clinically indistinguishable from carbamoyl phosphate synthetase 1 deficiency, rendering the identification of NAGS gene mutations key for differentiation, which is crucial, as only NAGSD has substitutive therapy. Over the last 13 years, we have identified 43 patients from 33 families with NAGS mutations, of which 14 were novel. Overall, 36 NAGS mutations have been found so far in 56 patients from 42 families, of which 76% are homozygous for the mutant allele. 61% of mutations are missense changes. Lack or decrease of NAGS protein is predicted for ∼1/3 of mutations. Missense mutations frequency is inhomogeneous along NAGS: null for exon 1, but six in exon 6, which reflects the paramount substrate binding/catalytic role of the C-terminal domain (GNAT domain). Correspondingly, phenotypes associated with missense mutations mapping in the GNAT domain are more severe than phenotypes of amino acid kinase domain-mapping missense mutations. Enzyme activity and stability assays with 12 mutations introduced into pure recombinant Pseudomonas aeruginosa NAGS, together with in silico structural analysis, support the pathogenic role of most NAGSD-associated mutations found. The disease-causing mechanisms appear to be, from higher to lower frequency, decreased solubility/stability, aberrant kinetics/catalysis, and altered arginine modulation

Published
2016

32. ALDH18A1gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

Author

Panza, Emanuele, primary, Escamilla-Honrubia, Juan M., additional, Marco-Marín, Clara, additional, Gougeard, Nadine, additional, De Michele, Giuseppe, additional, Morra, Vincenzo Brescia, additional, Liguori, Rocco, additional, Salviati, Leonardo, additional, Donati, Maria Alice, additional, Cusano, Roberto, additional, Pippucci, Tommaso, additional, Ravazzolo, Roberto, additional, Németh, Andrea H., additional, Smithson, Sarah, additional, Davies, Sally, additional, Hurst, Jane A., additional, Bordo, Domenico, additional, Rubio, Vicente, additional, and Seri, Marco, additional

Published
2015
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33. Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine

Author

Martinelli, Diego, primary, Häberle, Johannes, additional, Rubio, Vicente, additional, Giunta, Cecilia, additional, Hausser, Ingrid, additional, Carrozzo, Rosalba, additional, Gougeard, Nadine, additional, Marco-Marín, Clara, additional, Goffredo, Bianca M., additional, Meschini, Maria Chiara, additional, Bevivino, Elsa, additional, Boenzi, Sara, additional, Colafati, Giovanna Stefania, additional, Brancati, Francesco, additional, Baumgartner, Matthias R., additional, and Dionisi-Vici, Carlo, additional

Published
2011
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34. Correction: The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation.

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczór, Miłosz, Mata, Carlos P., Krieger, James, Ruiz-Rodriguez, Paula, López-Redondo, Maria Luisa, Francés-Gómez, Clara, Melero, Roberto, Sánchez-Sorzano, Carlos Óscar, Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jeronimo, Rubio, Vicente, and Marina, Alberto

Subjects
SARS-CoV-2, SUCCESS
Abstract

In the Financial Disclosure, the number for the grant awarded by EPIDNA is incorrect. Reference 1 Ginex T, Marco-Marín C, Wieczór M, Mata CP, Krieger J, Ruiz-Rodriguez P, et al. (2022) The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation. [Extracted from the article]

Published
2022
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35. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: the case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczór, Miłosz, Mata, Carlos P., Krieger, James, López-Redondo, Maria Luisa, Francés-Gómez, Clara, Ruiz-Rodriguez, Paula, Melero, Roberto, Sánchez-Sorzano, Carlos Óscar, Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jeronimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscolla, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José-Maria, European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Comunidad de Madrid, European Research Council, Instituto de Salud Carlos III, Banco Santander, Generalitat Valenciana, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, López-Redondo, Marisa, Francés-Gómez, Clara, Ruiz-Rodríguez, Paula, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Subjects
0303 health sciences, 03 medical and health sciences, 010402 general chemistry, 01 natural sciences, 3. Good health, 030304 developmental biology, 0104 chemical sciences
Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has now reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness., This research work was supported by the European Commission–NextGenerationEU through the CSIC Global Health Platform. Additionally, authors would like to acknowledge economic support from the Spanish Ministry of Science and Innovation through Grants: PID2019-104757RB-I00 funded by MCIN/AEI/ 10.13039/501100011033, RTI2018-094399-A-I00, and “ERDF A way of making Europe”, by the “European Union”, Grant SEV 2017-0712 funded by MCIN/AEI /10.13039/501100011033, the “Comunidad Autónoma de Madrid" through Grant: S2017/BMD3817, and the European Union (EU) and Horizon 2020 through grants: Marie-Curie Fellowship EnLaCES (MSCA IF 2020, Proposal: 101024130) (to JK), HighResCells (ERC - 2018 - SyG, Proposal: 810057), and iNEXT-Discovery (Proposal: 871037). AM, VR, JB and JLL are funded by CIBERER-ISCIII (proposal: COV20/00437), Fondo Supera COVID-19 (proposal: CSICCOVID19-082), Banco Santander (Proposal: BlockAce), and CSIC PTI Salud Global (Proposal: 202080E110). VR is funded by the Spanish Ministry of Science and Innovation through Grant PID2020-120322RB-C21. IC is funded by project PID2019-104477RB-100, Fondo COVID COV20/00140 and ERC CoG 101001038. MC is funded by the RyC program from the Spanish Ministry of Science and Innovation, the Generalitat Valenciana (SEJI/2019/011).

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36. The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author

Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, The IBV-Covid19-Pipeline, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, Carazo, José M., European Commission, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Comunidad de Madrid, Banco Santander, Instituto de Salud Carlos III, Ginex, Tiziana [0000-0002-5739-8713], Marco-Marín, Clara [0000-0002-8813-3515], Wieczor, Milosz [0000-0003-4990-8629], Mata, Carlos P. [0000-0003-3381-7431], Krieger, James [0000-0001-6194-6244], Ruiz-Rodríguez, Paula [0000-0003-0727-5974], López-Redondo, Marisa [0000-0002-3328-6821], Francés-Gómez, Clara [0000-0001-7341-3824], Melero, Roberto [0000-0001-9467-9381], Sorzano, Carlos Óscar S. [0000-0002-9473-283X], Martínez, Marta [0000-0002-8435-5540], Gougeard, Nadine [0000-0001-7338-7267], Forcada-Nadal, Alicia [0000-0003-0179-4044], Zamora-Caballero, Sara [0000-0003-4717-8845], Gozalbo-Rovira, Roberto [0000-0003-3427-3800], Sanz-Frasquet, Carla [0000-0002-6990-3131], Arranz, Rocío [0000-0001-5321-0915], Bravo, Jerónimo [0000-0001-6695-2846], Rubio, Vicente [0000-0001-8124-1196], Marina, Alberto [0000-0002-1334-5273], Geller, Ron [0000-0002-7612-4611], Comas, Iñaki [0000-0001-5504-9408], Gil, Carmen [0000-0002-3882-6081], Coscollá, Mireia [0000-0003-0752-0538], Orozco, Modesto [0000-0002-8608-3278], Llácer, José Luis [0000-0001-5304-1795], Carazo, José M. [0000-0003-0788-8447], Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ginex, Tiziana, Marco-Marín, Clara, Wieczor, Milosz, Mata, Carlos P., Krieger, James, Ruiz-Rodríguez, Paula, López-Redondo, Marisa, Francés-Gómez, Clara, Melero, Roberto, Sorzano, Carlos Óscar S., Martínez, Marta, Gougeard, Nadine, Forcada-Nadal, Alicia, Zamora-Caballero, Sara, Gozalbo-Rovira, Roberto, Sanz-Frasquet, Carla, Arranz, Rocío, Bravo, Jerónimo, Rubio, Vicente, Marina, Alberto, Geller, Ron, Comas, Iñaki, Gil, Carmen, Coscollá, Mireia, Orozco, Modesto, Llácer, José Luis, and Carazo, José M.

Subjects
Vaccines, SARS-CoV-2, Mutació (Biologia), Immunology, COVID-19, Peptidyl-Dipeptidase A, Mutation (Biology), Vacunes, Infections, Microbiology, Infeccions, Virology, Mutation, Spike Glycoprotein, Coronavirus, Genetics, Humans, Receptors, Virus, Parasitology, Angiotensin-Converting Enzyme 2, Genetic Background, Molecular Biology, Protein Binding
Abstract

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness., In this research work, PRR and TG were supported by salaries from the European Commission–NextGenerationEU through the CSIC Global Health Platform established by EU Council Regulation 2020/2094. The authors would like to acknowledge economic support from: (a) the Spanish Ministry of Science and Innovation through grants: SEV-2017-0712 funded by MCIN/AEI/10.13039/501100011033 (CPM, JK, RM, COSS, MM, RA, JMC); 116880GB-I00 (JLL) and 120322RB-C21 (VR) funded within PID 2020; PID2019-104757RB-I00 funded by MCIN/AEI/10.13039/501100011033/ and “ERDF A way of making Europe”, by the “European Union” (JMC, COSS, RM, MM, CPM) and 104477RB-100 (IC) funded within PID 2019; RYC-2015-18213 (salary of MC) and RYC-2015-17517 (salary of RG) funded by the Ramon y Cajal fellowship program; RTI2018-094399-A-I00 (JMC, COSS, RM, CPM, MC) funded within the Retos Investigación program; the CRIOMECORR project funded as ESFRI-2019-01-CSIC-16; (b) the Horizon 2020 program through Marie Skłodowska-Curie Individual Fellowships EnLaCES (Proposal 101024130, salary of JK) and EPIDNA (Grant ID: 894498, salary of MW); (c) the European Research Council (ERC) through grants: ERC-2018-SyG-810057 HighResCells funded within the EXCELLENT SCIENCE program (JMC, MM, COSS, salary of RM), Grant 871037 iNEXT DISCOVERY (JMC, MM, COSS) and grant CoG-101001038 funded within the Consolidator Grants program (IC); (d) Generalitat Valenciana through grants: SEJI/2019/011 (MC) and SEJI/2019/030 (JLL); (e) Comunidad de Madrid through grant: S2017/BMD-3817 (JMC); (f) Santander Bank through grant: CSIC-COVID19-082 (AM, VR, JB, JLL, RG) funded through the Fondo Supera Covid-19; (g) Instituto de Salud Carlos III through grants: COV20/00437 (AM, VR, JB, JLL) and COV20/00140 (IC), both funded through the Fondos Covid-19 initiative; (h) Spanish National Research Council through grant: 202080E110 funded within the PTI Salud Global initiative (AM, VR, JB, JLL, RG).

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37. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism

Author

Giuseppe De Michele, Vicente Rubio, Domenico Bordo, Andrea H. Németh, Sally J. Davies, Jane A. Hurst, Roberto Cusano, Nadine Gougeard, Emanuele Panza, Juan Manuel Escamilla-Honrubia, Leonardo Salviati, Vincenzo Brescia Morra, Clara Marco-Marín, Marco Seri, Sarah F. Smithson, Rocco Liguori, Tommaso Pippucci, Maria Alice Donati, Roberto Ravazzolo, Panza, Emanuele, Escamilla-Honrubia, Juan M, Marco-Marín, Clara, Gougeard, Nadine, De Michele, Giuseppe, Brescia Morra, Vincenzo, Liguori, Rocco, Salviati, Leonardo, Donati, Maria Alice, Cusano, Roberto, Pippucci, Tommaso, Ravazzolo, Roberto, Németh, Andrea H, Smithson, Sarah, Davies, Sally, Hurst, Jane A, Bordo, Domenico, Rubio, Vicente, Seri, Marco, Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Escamilla-Honrubia, Juan Manuel, Escamilla Honrubia, Juan M, Marco Marín, Clara, DE MICHELE, Giuseppe, BRESCIA MORRA, Vincenzo, Rubio, Vicente [0000-0001-8124-1196], and Escamilla-Honrubia, Juan Manuel [0000-0003-0154-6569]

Subjects
0301 basic medicine, Male, Ornithine, Candidate gene, Mutagenesis (molecular biology technique), Biology, Gene mutation, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Congenital Bilateral Cataracts, medicine, Humans, Spastic Paraplegia, Gene, Loss function, Genetics, Mutation, Spastic Paraplegia, Hereditary, Medicine (all), Aldehyde Dehydrogenase, Phenotype, 030104 developmental biology, Hereditary, Female, Neurology (clinical), 030217 neurology & neurosurgery, Human
Abstract

8 páginas, 4 figuras, 1 tabla, Supported by Grants from the Comitato Telethon Fondazione Onlus, the Amministrazione Autonoma dei Monopoli di Stato, the city of Gubbio, Italy (grant numbers GGP06209 and GGP10121), the Italian Ministry of Health (‘Identification of tumor biomarkers through a biologydriven integrated approach’), and the Spanish and the Valencian Governments (grants BFU2011-30407 and Prometeo II/2014/029, respectively). NG holds a contract of CIBERER.

Published
2016

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