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1. TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development

Author

Woerden, G.M. van, Bos, M., Konink, C. de, Distel, B., Trezza, R. Avagliano, Shur, N.E., Barañano, K., Mahida, S., Chassevent, A., Schreiber, A., Erwin, A.L., Gripp, K.W., Rehman, F., Brulleman, S., McCormack, R., Geus, G. de, Kalsner, L., Sorlin, A., Bruel, A.L., Koolen, D.A., Gabriel, M.K., Rossi, M., Fitzpatrick, D.R., Wilkie, A.O.M., Calpena, E., Johnson, D., Brooks, A., Slegtenhorst, M. van, Fleischer, J., Groepper, D., Lindstrom, K., Innes, A. Micheil, Goodwin, A., Humberson, J., Noyes, A., Langley, K.G., Telegrafi, A., Blevins, A., Hoffman, J., Sacoto, M.J. Guillen, Juusola, J., Monaghan, K.G., Punj, S., Simon, M., Pfundt, R.P., Elgersma, Y., Kleefstra, T., Woerden, G.M. van, Bos, M., Konink, C. de, Distel, B., Trezza, R. Avagliano, Shur, N.E., Barañano, K., Mahida, S., Chassevent, A., Schreiber, A., Erwin, A.L., Gripp, K.W., Rehman, F., Brulleman, S., McCormack, R., Geus, G. de, Kalsner, L., Sorlin, A., Bruel, A.L., Koolen, D.A., Gabriel, M.K., Rossi, M., Fitzpatrick, D.R., Wilkie, A.O.M., Calpena, E., Johnson, D., Brooks, A., Slegtenhorst, M. van, Fleischer, J., Groepper, D., Lindstrom, K., Innes, A. Micheil, Goodwin, A., Humberson, J., Noyes, A., Langley, K.G., Telegrafi, A., Blevins, A., Hoffman, J., Sacoto, M.J. Guillen, Juusola, J., Monaghan, K.G., Punj, S., Simon, M., Pfundt, R.P., Elgersma, Y., and Kleefstra, T.

Abstract

Contains fulltext : 245113.pdf (Publisher’s version ) (Open Access), Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.

Published
2021

2. Mono-ubiquitination of Rabphilin 3A by UBE3A serves a non-degradative function

Author

Avagliano Trezza, R. (Rossella), Punt, A.M. (A. Mattijs), Mientjes, E.J. (Edwin), van den Berg, M. (Marlene), Zampeta, F.I. (F. Isabella), de Graaf, I.J. (Ilona J.), van der Weegen, Y. (Yana), Demmers, J.A.A. (Jeroen), Elgersma, Y. (Ype), Distel, B. (Ben), Avagliano Trezza, R. (Rossella), Punt, A.M. (A. Mattijs), Mientjes, E.J. (Edwin), van den Berg, M. (Marlene), Zampeta, F.I. (F. Isabella), de Graaf, I.J. (Ilona J.), van der Weegen, Y. (Yana), Demmers, J.A.A. (Jeroen), Elgersma, Y. (Ype), and Distel, B. (Ben)

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by brain-specific loss of UBE3A, an E3 ubiquitin protein ligase. A substantial number of possible ubiquitination targets of UBE3A have been identified, although evidence of being direct UBE3A substrates is often lacking. Here we identified the synaptic protein Rabphilin-3a (RPH3A), an effector of the RAB3A small GTPase involved in axonal vesicle priming and docking, as a ubiquitination target of UBE3A. We found that the UBE3A and RAB3A binding sites on RPH3A partially overlap, and that RAB3A binding to RPH3A interferes with UBE3A binding. We confirmed previous observations that RPH3A levels are critically dependent on RAB3A binding but, rather surprisingly, we found that the reduced RPH3A levels in the absence of RAB3A are not mediated by UBE3A. Indeed, while we found that RPH3A is ubiquitinated in a UBE3A-dependent manner in mouse brain, UBE3A mono-ubiquitinates RPH3A and does not facilitate RPH3A degradation. Moreover, we found that an AS-linked UBE3A missense mutation in the UBE3A region that interacts with RPH3A, abrogates the interaction with RPH3A. In conclusion, our results identify RPH3A as a novel target of UBE3A and suggest that UBE3A-dependent ubiquitination of RPH3A serves a non-degradative function.

Published
2021
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3. A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome

Author

Geerts-Haages, A., Bossuyt, S.N.V., Besten, I. den, Bruggenwirth, H., Burgt, I. van der, Yntema, H.G., Punt, A.M., Brooks, A., Elgersma, Y., Distel, B., Valstar, M., Geerts-Haages, A., Bossuyt, S.N.V., Besten, I. den, Bruggenwirth, H., Burgt, I. van der, Yntema, H.G., Punt, A.M., Brooks, A., Elgersma, Y., Distel, B., and Valstar, M.

Abstract

Contains fulltext : 229329.pdf (publisher's version ) (Open Access), BACKGROUND: Loss of functional UBE3A, an E3 protein ubiquitin ligase, causes Angelman syndrome (AS), a neurodevelopmental disorder characterized by severe developmental delay, speech impairment, epilepsy, movement or balance disorder, and a characteristic behavioral pattern. We identified a novel UBE3A sequence variant in a large family with eight affected individuals, who did not meet the clinical AS criteria. METHODS: Detailed clinical examination and genetic analysis was performed to establish the phenotypic diversity and the genetic cause. The function of the mutant UBE3A protein was assessed with respect to its subcellular localization, stability, and E3 ubiquitin ligase activity. RESULTS: All eight affected individuals showed the presence of a novel maternally inherited UBE3A sequence variant (NM_130838.4(UBE3A):c.1018-1020del, p.(Asn340del), which is in line with a genetic AS diagnosis. Although they presented with moderate to severe intellectual disability, the phenotype did not match the clinical criteria for AS. In line with this, functional analysis of the UBE3A p.Asn340del mutant protein revealed no major deficits in UBE3A protein localization, stability, or E3 ubiquitin ligase activity. CONCLUSION: The p.(Asn340del) mutant protein behaves distinctly different from previously described AS-linked missense mutations in UBE3A, and causes a phenotype that is markedly different from AS. This study further extends the range of phenotypes that are associated with UBE3A loss, duplication, or mutation.

Published
2020

4. A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome

Author

Geerts-Haages, A. (Amber), Bossuyt, S.N.V. (Stijn N. V.), Den Besten, I.E. (Inge E.), Brüggenwirth, H.T. (Hennie), Burgt, I. (Ineke) van der, Yntema, H.G., Punt, A.M. (A. Mattijs), Brooks, A.S. (Alice), Elgersma, Y. (Ype), Distel, B. (Ben), Valstar, M.J. (Marlies), Geerts-Haages, A. (Amber), Bossuyt, S.N.V. (Stijn N. V.), Den Besten, I.E. (Inge E.), Brüggenwirth, H.T. (Hennie), Burgt, I. (Ineke) van der, Yntema, H.G., Punt, A.M. (A. Mattijs), Brooks, A.S. (Alice), Elgersma, Y. (Ype), Distel, B. (Ben), and Valstar, M.J. (Marlies)

Abstract

Background: Loss of functional UBE3A, an E3 protein ubiquitin ligase, causes Angelman syndrome (AS), a neurodevelopmental disorder characterized by severe developmental delay, speech impairment, epilepsy, movement or balance disorder, and a characteristic behavioral pattern. We identified a novel UBE3A sequence variant in a large family with eight affected individuals, who did not meet the clinical AS criteria. Methods: Detailed clinical examination and genetic analysis was performed to establish the phenotypic diversity and the genetic cause. The function of the mutant UBE3A protein was assessed with respect to its subcellular localization, stability, and E3 ubiquitin ligase activity. Results: All eight affected individuals showed the presence of a novel maternally inherited UBE3A sequence variant (NM_130838.4(UBE3A):c.1018-1020del, p.(Asn340del), which is in line with a genetic AS diagnosis. Although they presented with moderate to severe intellectual disability, the phenotype did not match the clinical criteria for AS. In line with this, functional analysis of the UBE3A p.Asn340del mutant protein revealed no major deficits in UBE3A protein localization, stability, or E3 ubiquitin ligase activity. Conclusion: The p.(Asn340del) mutant protein behaves distinctly different from previously described AS-linked missense mutations in UBE3A, and causes a phenotype that is markedly different from AS. This study further extends the range of phenotypes that are associated with UBE3A loss, duplication, or mutation.

Published
2020
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6. A versatile plasmid system for reconstitution and analysis of mammalian ubiquitination cascades in yeast

Author

Trezza, R.A. (Rossella Avagliano), van den Burg, J. (Janny), van den Oever, N. (Nico), Distel, B. (Ben), Trezza, R.A. (Rossella Avagliano), van den Burg, J. (Janny), van den Oever, N. (Nico), and Distel, B. (Ben)

Abstract

Ubiquitination is a posttranslational protein modification that regulates most aspects of cellular life. The sheer number of ubiquitination enzymes that are present in a mammalian cell, over 700 in total, has thus far hampered the analysis of distinct protein ubiquitination cascades in a cellular context. To overcome this complexity we have developed a versatile vector system that allows the reconstitution of specific ubiquitination cascades in the model eukaryote Saccharomyces cerevisae (baker’s yeast). The vector system consists of 32 modular yeast shuttle plasmids allowing inducible or constitutive expression of up to four proteins of interest in a single cell. To demonstrate the validity of the system, we show that co-expression in yeast of the mammalian HECT type E3 ubiquitin ligase E6AP (E6-Associated Protein) and a model substrate faithfully recapitulates E6AP-dependent substrate ubiquitination and degradation. In addition, we show that the endogenous sumoylation pathway of S. cerevisiae can specifically sumoylate mouse PML (Promyelocytic leukemia protein). In conclusion, the yeast vector system described in this paper provides a versatile tool to study complex posttranslational modifications in a cellular setting.

Published
2018
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7. Regulating the human HECT E3 ligases

Author

Sluimer, J. (Jasper), Distel, B. (Ben), Sluimer, J. (Jasper), and Distel, B. (Ben)

Abstract

Ubiquitination, the covalent attachment of ubiquitin to proteins, by E3 ligases of the HECT (homologous to E6AP C terminus) family is critical in controlling diverse physiological pathways. Stringent control of HECT E3 ligase activity and substrate specificity is essential for cellular health, whereas deregulation of HECT E3s plays a prominent role in disease. The cell employs a wide variety of regulatory mechanisms to control HECT E3 activity and substrate specificity. Here, we summarize the current understanding of these regulatory mechanisms that control HECT E3 function. Substrate specificity is generally determined by interactions of adaptor proteins with domains in the N-terminal extensions of HECT E3 ligases. These N-terminal domains have also been found to interact with the HECT domain, resulting in the formation of inhibitory conformations. In addition, catalytic activity of the HECT domain is commonly regulated at the level of E2 recruitment and through HECT E3 oligomerization. The previously mentioned regulatory mechanisms can be controlled through protein–protein interactions, post-translational modifications, the binding of calcium ions, and more. Functional activity is determined not only by substrate recruitment and catalytic activity, but also by the type of ubiquitin polymers catalyzed to the substrate. While this is often determined by the specific HECT member, recent studies demonstrate that HECT E3s can be modulated to alter the type of ubiquitin polymers they catalyze. Insight into these diverse regulatory mechanisms that control HECT E3 activity may open up new avenues for therapeutic strategies aimed at inhibition or enhancement of HECT E3 function in disease-related pathways.

Published
2018
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8. Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Author

Vrij, F.M.S. (Femke), Bouwkamp, C.G. (Christian), Gunhanlar, N. (Nilhan), Shpak, G. (Guy), Lendemeijer, B. (Bas), Baghdadi, M. (Maarouf), Gopalakrishna, S. (Shreekara), Ghazvini, M. (Mehrnaz), Li, T. (Tracy), Quadri, M. (Marialuisa), Olgiati, S. (Simone), Breedveld, G.J. (Guido), Coesmans, M.P.H. (Michiel), Mientjes, E.J. (Edwin), de Wit, T. (Ton), Verheijen, F.W. (Frans), Beverloo, H.B. (Berna), Cohen, D. (Dan), Kok, R.M. (Rob M.), Bakker, P.R. (Roberto), Nijburg, A. (Aviva), Spijker, A.T. (Anne), Haffmans, P.M.J. (P.M. Judith), Hoencamp, E. (Erik), Bergink, V. (Veerle), Vorstman, J.A.S., Wu, T. (Timothy), Olde Loohuis, L.M. (Loes M.), Amin, N. (Najaf), Langen, C.D. (Carolyn), Hofman, A. (Albert), Hoogendijk, W.J.G. (Witte), van Duijn, C.M. (Cornelia M.), Ikram, M.A. (M. A.), Vernooij, M.W. (Meike), Tiemeier, H.W. (Henning), Uitterlinden, A.G. (André G.), Elgersma, Y. (Ype), Distel, B. (Ben), Gribnau, J.H. (Joost), White, T.J.H. (Tonya), Bonifati, V. (Vincenzo), Kushner, S.A. (Steven A.), Vrij, F.M.S. (Femke), Bouwkamp, C.G. (Christian), Gunhanlar, N. (Nilhan), Shpak, G. (Guy), Lendemeijer, B. (Bas), Baghdadi, M. (Maarouf), Gopalakrishna, S. (Shreekara), Ghazvini, M. (Mehrnaz), Li, T. (Tracy), Quadri, M. (Marialuisa), Olgiati, S. (Simone), Breedveld, G.J. (Guido), Coesmans, M.P.H. (Michiel), Mientjes, E.J. (Edwin), de Wit, T. (Ton), Verheijen, F.W. (Frans), Beverloo, H.B. (Berna), Cohen, D. (Dan), Kok, R.M. (Rob M.), Bakker, P.R. (Roberto), Nijburg, A. (Aviva), Spijker, A.T. (Anne), Haffmans, P.M.J. (P.M. Judith), Hoencamp, E. (Erik), Bergink, V. (Veerle), Vorstman, J.A.S., Wu, T. (Timothy), Olde Loohuis, L.M. (Loes M.), Amin, N. (Najaf), Langen, C.D. (Carolyn), Hofman, A. (Albert), Hoogendijk, W.J.G. (Witte), van Duijn, C.M. (Cornelia M.), Ikram, M.A. (M. A.), Vernooij, M.W. (Meike), Tiemeier, H.W. (Henning), Uitterlinden, A.G. (André G.), Elgersma, Y. (Ype), Distel, B. (Ben), Gribnau, J.H. (Joost), White, T.J.H. (Tonya), Bonifati, V. (Vincenzo), and Kushner, S.A. (Steven A.)

Abstract

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

Published
2018
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9. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Kury, S., Woerden, G.M. van, Besnard, T., Onori, M.P., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., Stessman, H.A.F., Pujol, A., Distel, B., Robak, L.A., Bernstein, J.A., Denomme-Pichon, A.S., Lesca, G., Sellars, E.A., Berg, J ., Carre, W., Busk, O.L., Bon, B.W.M. van, Waugh, J.L., Deardorff, M., Hoganson, G.E., Bosanko, K.B., Johnson, D.S., Dabir, T., Holla, O.L., Sarkar, A., Tveten, K., Bellescize, J. de, Braathen, G.J., Terhal, P.A., Grange, D.K., Haeringen, A. van, Lam, C., Mirzaa, G., Burton, J., Bhoj, E.J., Douglas, J., Santani, A.B., Nesbitt, A.I., Helbig, K.L., Andrews, M.V., Begtrup, A., Tang, S., Gassen, K.L.I. van, Juusola, J., Foss, K., Enns, G.M., Moog, U., Hinderhofer, K., Paramasivam, N., Lincoln, S., Kusako, B.H., Lindenbaum, P., Charpentier, E., Nowak, C.B., Cherot, E., Simonet, T., Ruivenkamp, C.A.L., Hahn, S., Brownstein, C.A., Xia, F., Schmitt, S., Deb, W., Bonneau, D., Nizon, M., Quinquis, D., Chelly, J., Rudolf, G., Sanlaville, D., Parent, P., Gilbert-Dussardier, B., Toutain, A., Sutton, V.R., Thies, J., Peart-Vissers, L.E.L.M., Boisseau, P., Vincent, M., Grabrucker, A.M., Dubourg, C., Tan, W.H., Verbeek, N.E., Granzow, M., Santen, G.W.E., Shendure, J., Isidor, B., Pasquier, L., Redon, R., Yang, Y, State, M.W., Kleefstra, T., Cogne, B., Petrovski, S., Retterer, K., Eichler, E.E., Rosenfeld, J.A., Agrawal, P.B., Elgersma, Y., Kury, S., Woerden, G.M. van, Besnard, T., Onori, M.P., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., Stessman, H.A.F., Pujol, A., Distel, B., Robak, L.A., Bernstein, J.A., Denomme-Pichon, A.S., Lesca, G., Sellars, E.A., Berg, J ., Carre, W., Busk, O.L., Bon, B.W.M. van, Waugh, J.L., Deardorff, M., Hoganson, G.E., Bosanko, K.B., Johnson, D.S., Dabir, T., Holla, O.L., Sarkar, A., Tveten, K., Bellescize, J. de, Braathen, G.J., Terhal, P.A., Grange, D.K., Haeringen, A. van, Lam, C., Mirzaa, G., Burton, J., Bhoj, E.J., Douglas, J., Santani, A.B., Nesbitt, A.I., Helbig, K.L., Andrews, M.V., Begtrup, A., Tang, S., Gassen, K.L.I. van, Juusola, J., Foss, K., Enns, G.M., Moog, U., Hinderhofer, K., Paramasivam, N., Lincoln, S., Kusako, B.H., Lindenbaum, P., Charpentier, E., Nowak, C.B., Cherot, E., Simonet, T., Ruivenkamp, C.A.L., Hahn, S., Brownstein, C.A., Xia, F., Schmitt, S., Deb, W., Bonneau, D., Nizon, M., Quinquis, D., Chelly, J., Rudolf, G., Sanlaville, D., Parent, P., Gilbert-Dussardier, B., Toutain, A., Sutton, V.R., Thies, J., Peart-Vissers, L.E.L.M., Boisseau, P., Vincent, M., Grabrucker, A.M., Dubourg, C., Tan, W.H., Verbeek, N.E., Granzow, M., Santen, G.W.E., Shendure, J., Isidor, B., Pasquier, L., Redon, R., Yang, Y, State, M.W., Kleefstra, T., Cogne, B., Petrovski, S., Retterer, K., Eichler, E.E., Rosenfeld, J.A., Agrawal, P.B., and Elgersma, Y.

Abstract

Contains fulltext : 182539.pdf (publisher's version ) (Closed access), Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017

10. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Küry, S. (Sébastien), Woerden, G.M. (Geeske) van, Besnard, T. (Thomas), Proietti-Onori, M. (Martina), Latypova, X. (Xénia), Towne, M.C. (Meghan C.), Cho, M.T. (Megan T.), Prescott, T. (Trine), Ploeg, M.A. (Melissa), Sanders, S. (Stephan), Stessman, H.A.F. (Holly A F), Pujol, A. (Aurora), Distel, B. (Ben), Robak, L.A. (Laurie A.), Bernstein, J.A. (Jonathan A.), Denommé-Pichon, A.-S. (Anne-Sophie), Lesca, G. (Gaëtan), Sellars, E.A. (Elizabeth A.), Berg, J. (Jonathan), Carré, W. (Wilfrid), Busk, ØL. (Øyvind Løvold), Bon, B. (Bregje) van, Waugh, J.L. (Jeff L.), Deardorff, M.A. (Matthew), Hoganson, G.E. (George E.), Bosanko, K.B. (Katherine B.), Johnson, D.S. (Diana S.), Dabir, T. (Tabib), Holla, ØL. (Øystein Lunde), Sarkar, A. (Ajoy), Tveten, K. (Kristian), de Bellescize, J. (Julitta), Braathen, G.J. (Geir J.), Terhal, P. (Paulien), Grange, D.K. (Dorothy K.), Haeringen, A. (Arie) van, Lam, C. (Christina), Mirzaa, G.M. (Ghayda), Burton, J. (Jennifer), Bhoj, E.J. (Elizabeth J.), Douglas, J. (Jessica), Santani, A.B. (Avni B.), Nesbitt, A.I. (Addie I.), Helbig, K.L. (Katherine L.), Andrews, M.V. (Marisa V.), Begtrup, A. (Amber), Tang, S. (Sha), van Gassen, K.L.I. (Koen L.I.), Juusola, J. (Jane), Foss, K. (Kimberly), Enns, G. (Gregory), Moog, U. (Ute), Hinderhofer, K. (Katrin), Paramasivam, N. (Nagarajan), Lincoln, S. (Sharyn), Kusako, B.H. (Brandon H.), Lindenbaum, P. (Pierre), Charpentier, E. (Eric), Nowak, C.B. (Catherine B.), Cherot, E. (Elouan), Simonet, T. (Thomas), Ruivenkamp, C.A. (Claudia), Hahn, S. (Sihoun), Brownstein, C.A. (Catherine A.), Xia, F. (Fan), Schmitt, S. (Sébastien), Deb, W. (Wallid), Bonneau, D. (Dominique), Nizon, M. (Mathilde), Quinquis, D. (Delphine), Chelly, J. (Jamel), Rudolf, G. (Gabrielle), Sanlaville, D. (Damien), Parent, P. (Philippe), Gilbert-Dussardier, B. (Brigitte), Toutain, A. (Annick), Sutton, V.R. (V. Reid), Thies, J. (Jenny), Peart-Vissers, L.E.L.M. (Lisenka E L M), Boisseau, P. (Pierre), Vincent, M. (Marie), Grabrucker, A.M. (Andreas M.), Dubourg, C. (Christèle), Tan, W.-H. (Wen-Hann), Verbeek, N.E. (Nienke), Granzow, M. (Martin), Santen, G.W.E. (Gijs), Shendure, J. (Jay), Isidor, B. (Bertrand), Pasquier, L. (Laurent), Redon, R. (Richard), Yang, Y. (Yaping), State, M.W. (Matthew), Kleefstra, T. (Tjitske), Cogné, B. (Benjamin), Petrovski, S. (Slavé), Retterer, K. (Kyle), Eichler, E.E. (Evan), Rosenfeld, J.A. (Jill), Agrawal, P.B. (Pankaj B.), Bézieau, S. (Stéphane), Odent, S. (Sylvie), Elgersma, Y. (Ype), Mercier, S. (Sandra), Küry, S. (Sébastien), Woerden, G.M. (Geeske) van, Besnard, T. (Thomas), Proietti-Onori, M. (Martina), Latypova, X. (Xénia), Towne, M.C. (Meghan C.), Cho, M.T. (Megan T.), Prescott, T. (Trine), Ploeg, M.A. (Melissa), Sanders, S. (Stephan), Stessman, H.A.F. (Holly A F), Pujol, A. (Aurora), Distel, B. (Ben), Robak, L.A. (Laurie A.), Bernstein, J.A. (Jonathan A.), Denommé-Pichon, A.-S. (Anne-Sophie), Lesca, G. (Gaëtan), Sellars, E.A. (Elizabeth A.), Berg, J. (Jonathan), Carré, W. (Wilfrid), Busk, ØL. (Øyvind Løvold), Bon, B. (Bregje) van, Waugh, J.L. (Jeff L.), Deardorff, M.A. (Matthew), Hoganson, G.E. (George E.), Bosanko, K.B. (Katherine B.), Johnson, D.S. (Diana S.), Dabir, T. (Tabib), Holla, ØL. (Øystein Lunde), Sarkar, A. (Ajoy), Tveten, K. (Kristian), de Bellescize, J. (Julitta), Braathen, G.J. (Geir J.), Terhal, P. (Paulien), Grange, D.K. (Dorothy K.), Haeringen, A. (Arie) van, Lam, C. (Christina), Mirzaa, G.M. (Ghayda), Burton, J. (Jennifer), Bhoj, E.J. (Elizabeth J.), Douglas, J. (Jessica), Santani, A.B. (Avni B.), Nesbitt, A.I. (Addie I.), Helbig, K.L. (Katherine L.), Andrews, M.V. (Marisa V.), Begtrup, A. (Amber), Tang, S. (Sha), van Gassen, K.L.I. (Koen L.I.), Juusola, J. (Jane), Foss, K. (Kimberly), Enns, G. (Gregory), Moog, U. (Ute), Hinderhofer, K. (Katrin), Paramasivam, N. (Nagarajan), Lincoln, S. (Sharyn), Kusako, B.H. (Brandon H.), Lindenbaum, P. (Pierre), Charpentier, E. (Eric), Nowak, C.B. (Catherine B.), Cherot, E. (Elouan), Simonet, T. (Thomas), Ruivenkamp, C.A. (Claudia), Hahn, S. (Sihoun), Brownstein, C.A. (Catherine A.), Xia, F. (Fan), Schmitt, S. (Sébastien), Deb, W. (Wallid), Bonneau, D. (Dominique), Nizon, M. (Mathilde), Quinquis, D. (Delphine), Chelly, J. (Jamel), Rudolf, G. (Gabrielle), Sanlaville, D. (Damien), Parent, P. (Philippe), Gilbert-Dussardier, B. (Brigitte), Toutain, A. (Annick), Sutton, V.R. (V. Reid), Thies, J. (Jenny), Peart-Vissers, L.E.L.M. (Lisenka E L M), Boisseau, P. (Pierre), Vincent, M. (Marie), Grabrucker, A.M. (Andreas M.), Dubourg, C. (Christèle), Tan, W.-H. (Wen-Hann), Verbeek, N.E. (Nienke), Granzow, M. (Martin), Santen, G.W.E. (Gijs), Shendure, J. (Jay), Isidor, B. (Bertrand), Pasquier, L. (Laurent), Redon, R. (Richard), Yang, Y. (Yaping), State, M.W. (Matthew), Kleefstra, T. (Tjitske), Cogné, B. (Benjamin), Petrovski, S. (Slavé), Retterer, K. (Kyle), Eichler, E.E. (Evan), Rosenfeld, J.A. (Jill), Agrawal, P.B. (Pankaj B.), Bézieau, S. (Stéphane), Odent, S. (Sylvie), Elgersma, Y. (Ype), and Mercier, S. (Sandra)

Abstract

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017
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11. Biogenesis of Peroxisomes

Author

Tabak, H. F., Distel, B., Tager, Joseph M., editor, Azzi, Angelo, editor, Papa, Sergio, editor, and Guerrieri, Ferruccio, editor

Published
1989
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12. Pex8p, an intraperoxisomal peroxin of Saccharomyces cerevisiae required for protein transport into peroxisomes binds the PTS1 receptor Pex5p

Author

Rehling, P, Skaletz-Rorowski, A, Girzalsky, W, Voorn-Brouwer, T, Franse, MM, Distel, B, Veenhuis, M, Kunau, WH, Erdmann, R, Kunau, Wolf-H., Other departments, Electron Microscopy, Groningen Biomolecular Sciences and Biotechnology, and Molecular Cell Biology

Subjects
Saccharomyces cerevisiae Proteins, Peroxisome-Targeting Signal 1 Receptor, Molecular Sequence Data, Saccharomyces cerevisiae, Receptors, Cytoplasmic and Nuclear, COLI SHUTTLE VECTORS, Peroxin, GENE ENCODES, Biochemistry, Fungal Proteins, Peroxins, 3-OXOACYL-COA THIOLASE, RESTRICTION SITES, Peroxisomes, YEAST, Amino Acid Sequence, Molecular Biology, Peroxisomal targeting signal, biology, Peroxisomal matrix, TARGETING SIGNAL, Peroxisomal Targeting Signal 1, IMPORT, Membrane Transport Proteins, Biological Transport, Cell Biology, Peroxisome, biology.organism_classification, Transport protein, Cytosol, PICHIA-PASTORIS, MATRIX PROTEINS, Mutation, Carrier Proteins, Sequence Alignment, HANSENULA-POLYMORPHA
Abstract

We report the characterization of ScPex8p, which is essential for peroxisomal biogenesis in Saccharomyces cerevisiae, Cells lacking Pex8p are characterized by the presence of peroxisomal membrane ghosts and mislocalization of peroxisomal matrix proteins of the PTS1 and PTS2 variety to the cytosol, Pex8p is tightly associated with the lumenal face of the peroxisomal membrane, Consistent with its intraperoxisomal localization, Pex8p contains a peroxisomal targeting signal 1, and it interacts with the PTS1 receptor Pex5p. However, the Pex5p/Pex8p association is also observed upon deletion of the PTS1 of Pex8p, suggesting that Pex8p contains a second binding site for Pex5p. The pex8 Delta mutant phenotype and the observed PTS1-independent interaction with the PTSI receptor suggest that Pex8p is involved in protein import into the peroxisomal matrix. In pex8 Delta cells, the PTS1 and PTS2 receptor still associate with membrane bound components of the protein import machinery, supporting the assumption that the Pex8p function in protein translocation follows the docking event.

Published
2000

14. Ubiquitin: a new player in the peroxisome field

Author

Kragt, A., Benne, R., Distel, B., Mayer, R. J., Ciechanover, A., Rechsteiner, M., Medical Biochemistry, Amsterdam institute for Infection and Immunity, and Amsterdam Gastroenterology Endocrinology Metabolism

Published
2006

15. Purification of yeast peroxisomes

Author

Distel, B., Kragt, A., Xiao, W., Amsterdam institute for Infection and Immunity, Amsterdam Gastroenterology Endocrinology Metabolism, and Medical Biochemistry

Published
2006

21. Peroxisome isolation

Author

Distel, B., van der Leij, I., Kos, W., and Other departments

Published
1996

23. Pex4p-Pex22p structure

Author

Williams, C., primary, van den Berg, M., additional, Panjikar, S., additional, Distel, B., additional, and Wilmanns, M., additional

Published
2011
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24. The carboxyl-terminal tripeptide serine-lysine-leucine of firefly luciferase is necessary but not sufficient for peroxisomal import in yeast

Author

Distel, B., Gould, S. J., Voorn-Brouwer, T., van der Berg, M., Tabak, H. F., Subramani, S., and Other departments

Abstract

Firefly luciferase is imported into peroxisomes in insects, mammals, plants, and yeast, which implies that the mechanism of protein translocation into peroxisomes has been conserved during eukaryotic evolution. The carboxyl-terminal tripeptide serine-lysine-leucine in luciferase acts as a peroxisomal import signal in mammalian cells. We have investigated whether this tripeptide is also involved in translocation of firefly luciferase into peroxisomes in yeast (Saccharomyces cerevisiae). We show by gene fusion experiments that the carboxyl-terminal 104 amino acids of luciferase can direct a heterologous protein to yeast peroxisomes. Luciferase mutant proteins were tested for their ability to be imported into yeast peroxisomes in vivo. We demonstrate that mutations in the carboxyl-terminal serine-lysine-leucine tripeptide abolish translocation of the protein into yeast peroxisomes. However, when a passenger protein was tagged at its carboxyl terminus with this tripeptide the fusion protein did not go to peroxisomes. These results indicate that, in yeast, the tripeptide is necessary but not sufficient for peroxisomal import

Published
1992

30. A unified nomenclature for peroxisome biogenesis factors.

Author

Distel, B, primary, Erdmann, R, additional, Gould, S J, additional, Blobel, G, additional, Crane, D I, additional, Cregg, J M, additional, Dodt, G, additional, Fujiki, Y, additional, Goodman, J M, additional, Just, W W, additional, Kiel, J A, additional, Kunau, W H, additional, Lazarow, P B, additional, Mannaerts, G P, additional, Moser, H W, additional, Osumi, T, additional, Rachubinski, R A, additional, Roscher, A, additional, Subramani, S, additional, Tabak, H F, additional, Tsukamoto, T, additional, Valle, D, additional, van der Klei, I, additional, van Veldhoven, P P, additional, and Veenhuis, M, additional

Published
1996
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41. Import of alcohol oxidase into peroxisomes of Saccharomyces cerevisiae.

Author

Distel, B., Veenhuis, M., and Tabak, H. F.

Abstract

Saccharomyces cerevisiae is unable to grow on methanol because it lacks the enzymes required for its metabolism. To study the possibility of whether or not the methanol oxidation pathway of Hansenula polymorpha can be transferred to S. cerevisiae, the gene coding for alcohol oxidase, a peroxisomal homo‐octameric flavoprotein, was introduced into S. cerevisiae. Transformed cells contain varying amounts of alcohol oxidase depending on the plasmid used. Immunocytochemical experiments indicate that the protein is imported into peroxisomes, whether organelle proliferation is induced or not. Cells lack alcohol oxidase activity however, and only the monomeric, non‐functional, form of the protein is found. These findings indicate that the H. polymorpha peroxisomal targeting signal of alcohol oxidase is recognized in S. cerevisiae and protein monomers are imported.

Published
1987
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42. Alcohol oxidase expressed under nonmethylotrophic conditions is imported, assembled, and enzymatically active in peroxisomes of Hansenula polymorpha.

Author

Distel, B, Van der Leÿ, I, Veenhuis, M, and Tabak, H F

Abstract

We have introduced into Hansenula polymorpha an extra copy of its alcohol oxidase gene. This gene which is under the control of the Saccharomyces cerevisiae phosphoglycerate kinase promoter is integrated in a chromosome different from the one containing the endogenous gene. Cells with the extra alcohol oxidase gene, grown on glucose or ethanol as the sole carbon source, express enzymatically active alcohol oxidase. However, other enzymes characteristic for methylotrophic growth conditions are absent or present at low levels. Most of the alcohol oxidase occurs in the octameric state and immuno- and cytochemical evidence shows that it is located in a single enlarged peroxisome per cell. Such peroxisomes show crystalloid inclusions which are lacking in the peroxisomes present in glucose grown control cells. Our results suggest that import into peroxisomes of H. polymorpha, assembly and activation of alcohol oxidase is not conditionally dependent on adaptation to methylotrophic growth conditions and that proliferation of peroxisomes is a well-programmed process that is not triggered solely by overproduction of a peroxisomal protein.

Published
1988
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43. Basolateral sorting of the cation-dependent mannose 6-phosphate receptor in Madin-Darby canine kidney cells. Identification of a basolateral determinant unrelated to clathrin-coated pit localization signals.

Author

Distel, B, Bauer, U, Le Borgne, R, and Hoflack, B

Abstract

In polarized Madin-Darby canine kidney (MDCK) cells, sorting of membrane proteins in the trans-Golgi network for basolateral delivery depends on the presence of cytoplasmic determinants that are related or unrelated to clathrin-coated pit localization signals. Whether these signals mediate basolateral protein sorting through common or distinct pathways is unknown. The cytoplasmic domain of the cation-dependent mannose 6-phosphate receptor (CD-MPR) contains clathrin-coated pit localization signals that are necessary for endocytosis and lysosomal enzyme targeting. In this study, we have addressed the function of these signals in polarized sorting of the CD-MPR. A chimeric protein, made of the luminal domain of the influenza virus hemagglutinin fused to the transmembrane and cytoplasmic domains of the CD-MPR was stably expressed in MDCK cells. This chimera (HCD) is able to interact with the AP-1 Golgi-specific assembly proteins and is detected on the basolateral plasma membrane of MDCK cells where it is endocytosed. Deletion analysis and site-directed mutagenesis of the cytoplasmic domain of the CD-MPR indicate that HCD chimeras devoid of clathrin-coated pit localization signals are still transported to the basolateral membrane where they accumulate. A HCD chimera containing only the transmembrane domain and the 12 membrane-proximal amino acids of the CD-MPR cytoplasmic tail is also found on the basolateral membrane but is unable to interact with the AP-1 assembly proteins. However, the overexpression of this mutant results in partial apical delivery. It is concluded, therefore, that the basolateral transport of this chimera requires a saturable sorting machinery distinct from AP-1.

Published
1998

44. Analysis of the carboxyl-terminal peroxisomal targeting signal 1 in a homologous context in Saccharomyces cerevisiae.

Author

Elgersma, Y, Vos, A, van den Berg, M, van Roermund, C W, van der Sluijs, P, Distel, B, and Tabak, H F

Abstract

Most peroxisomal matrix proteins contain a carboxyl-terminal tripeptide that directs them to peroxisomes. Within limits, these amino acids may be varied, without loss of function. The specificity of this peroxisomal targeting signal (PTS1) is remarkable considering its small size and its relaxed consensus sequence. Moreover, several peroxisomal proteins have a PTS1-like signal that does not fit the reported consensus sequence. Because many of these PTS1 variants seem to be functional in a species-dependent or protein context-dependent manner, we investigated the PTS1 requirements in a homologous context, using Saccharomyces cerevisiae and endogenous peroxisomal malate dehydrogenase (MDH3). Peroxisomal import of the MDH3-PTS1 variants was tested qualitatively by the ability to complement the Deltamdh3 mutant and quantitatively by subcellular fractionation. We observed efficient import of MDH3 into peroxisomes with a large variety of PTS1 tripeptides. Many of these variants do not fit the observed PTS1 requirements for heterologously expressed proteins, which suggests that additional domains in the protein may be of decisive importance whether or not a certain PTS1 variant is recognized by the components of the peroxisomal import machinery. Because we show that dimerization of MDH3 precedes import into the organelle, these domains are most likely conformational domains.

Published
1996

45. Inhibition of human coagulation factor VIII by monoclonal antibodies. Mapping of functional epitopes with the use of recombinant factor VIII fragments

Author

Leyte, A, Mertens, K, Distel, B, Evers, R F, De Keyzer-Nellen, M J M, Groenen-Van Dooren, M M C L, De Bruin, J, Pannekoek, H, Van Mourik, J A, and Verbeet, M P

Abstract

The epitopes of four monoclonal antibodies against coagulation Factor VIII were mapped with the use of recombinant DNA techniques. Full-length Factor VIII cDNA and parts thereof were inserted into the vector pSP64, permitting transcription in vitro with the use of a promoter specific for SP6 RNA polymerase. Factor VIII DNA inserts were truncated from their 3′-ends by selective restriction-enzyme digestion and used as templates for ‘run-off’ mRNA synthesis. Translation in vitro with rabbit reticulocyte lysate provided defined radiolabelled Factor VIII fragments for immunoprecipitation studies. Two antibodies are shown to be directed against epitopes on the 90 kDa chain of Factor VIII, between residues 712 and 741. The 80 kDa chain appeared to contain the epitopes of the other two antibodies, within the sequences 1649-1778 and 1779-1840 respectively. The effect of antibody binding to these sequences was evaluated at two distinct levels within the coagulation cascade. Both Factor VIII procoagulant activity and Factor VIII cofactor function in Factor Xa generation were neutralized upon binding to the region 1779-1840. The antibodies recognizing the region 713-740 or 1649-1778, though interfering with Factor VIII procoagulant activity, did not inhibit in Factor Xa generation. These findings demonstrate that antibodies that virtually inhibit Factor VIII in coagulation in vitro are not necessarily directed against epitopes involved in Factor VIII cofactor function. Inhibition of procoagulant activity rather than of cofactor function itself may be explained by interference in proteolytic activation of Factor VIII. This hypothesis is in agreement with the localization of the epitopes in the proximity of thrombin-cleavage or Factor Xa-cleavage sites.

Published
1989
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48. The localization and function of the UBE3A E3 ligase in Angelman syndrome

Author

Bossuyt, S.N.V., Distel, B., Elgersma, Y., de Vries, C.J.M., and Faculteit der Geneeskunde

Subjects
congenital, hereditary, and neonatal diseases and abnormalities
Abstract

The contents of this thesis focus on Angelman Syndrome (AS), a rare neurodevelopmental disorder. More specifically, it focuses on the protein central to the disorder and its function. highlights a key difference between the different isoforms of UBE3A. This chapter exposes the difference in subcellular localization between UBE3A isoforms, and shows that mice lacking the dominant nuclear form most faithfully recapitulate the phenotypes associated with AS. Through creative use of molecular biology techniques these experiments demonstrate not only the precise mechanism through which the dominant isoform localizes to the nucleus of the cell, but also how AS-linked missense mutations abrogate this nuclear targeting. The structural requirements of the UBE3A AZUL interaction with its transport are further elucidated by highlighting the specific contributions of both UBE3A and PSMD4. Mutations causing AS are further analyzed and, showing almost half of AS-linked missense variants lead to mislocalization of UBE3A. Furthermore, by subjecting over 25 variants to a three-step functional analysis, this chapter has proposed a mutation classification system which clearly indicates that the main causes of aberrant function by UBE3A are caused either by mislocalization to the cytosol, or loss of catalytic activity in the nucleus. Concludingly, the results propose a framework where through experimental analysis, patient mutations can be grouped into specific categories.

Published
2022

49. A matter of perspective: The multifaceted role of UBE3A in Angelman syndrome development

Author

Avagliano Trezza, R., Distel, B., Zelcer, N., Aerts, Johannes M.F.G., Faculteit der Geneeskunde, Distel, Bernard, Zelcer, Noam, Aerts, Johannes M. F. G., Graduate School, and Medical Biochemistry

Subjects
congenital, hereditary, and neonatal diseases and abnormalities
Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutation or deletion of the UBE3A gene, which encodes an E3 ubiquitin protein ligase. E3 ligases are essential components of the UPS (ubiquitin proteasome system). The UPS is a finely tuned machinery that has an essential role in cellular homeostasis, and any perturbation of the UPS may lead to irreparable cellular damage. In this thesis we have employed molecular and biochemical techniques to unravel how the loss-of-function (deletion or mutations) of the E3 ubiquitin protein ligase UBE3A results in AS development, with emphasis on the identification and characterization of brain-specific targets of UBE3A. Using protein-protein interaction techniques we have identified several bona fide UBE3A interacting proteins, among which a pre-synaptic protein. Detailed biochemical and mutational analyses of these proteins have provided the first insights into the intracellular pathways where UBE3A exerts its function. By studying the localization of UBE3A isoforms we uncovered that UBE3A is predominantly localized in the nucleus and that AS-linked mutations can disturb nuclear localization. These observations suggest that UBE3A has an important role in the nucleus, providing further direction for future studies on the relation between UBE3A subcellular localization and the pathophysiology of AS.

Published
2019

50. Understanding the role of BAR and SH3 domain-containing proteins in fungi

Author

Gkourtsa, A., Aerts, Johannes M. F. G., Distel, Bernard, Hochstenbach, Frans M. H., Graduate School, Other departments, Amsterdam Gastroenterology Endocrinology Metabolism, Aerts, Johannes M.F.G., Distel, B., Hochstenbach, F.M.H., and Faculteit der Geneeskunde

Abstract

This thesis addresses the role of SH3 and BAR domain-containing proteins in different fungal species. SH3 domains are small modules that mediate protein-protein interactions and BAR domains are dimerization domains with membrane binding and bending properties. It is known that the ScRvs167 protein interacts via its SH3 domain with other components of the yeast endocytic machinery while its BAR domain dimerizes with the BAR domain of ScRvs161 and as a heterodimer complex is responsible for the membrane deformation that is crucial to vesicle formation as well as release of the vesicle from the plasma membrane in S. cerevisiae. In Chapter 2, we characterize a novel N-BAR heterodimer in C. albicans that consists of the Rvs162 and Rvs167-3 proteins and we show that in contrast to Rvs161/Rvs167 heterodimer it does not have an endocytic role. In Chapter 3 we demonstrate fission yeast proteins Hob1 and Hob3 (homologs of S. cerevisiae Rvs167 and Rvs161, respectively) ability to form heterodimers in vitro even though evidence suggests they have different functions. Sfp47, a novel F-BAR protein in S. pombe is the focus of Chapter 4. In the last two chapters we are focusing on SH3 domains and their interaction with peptide ligands. In Chapter 5 we investigate the evolution of SH3 domain-mediated interactions in fungi. In Chapter 6 we investigate the CaRvs167-3 SH3 domain: peptide ligand interaction. We conclude that CaRvs167-3 SH3 domain can bind to a peptide completely devoid of proline residues and we establish a novel binding sequence for the Rvs167-3 SH3.

Published
2017

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