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Sumoylation inhibits α-synuclein aggregation and toxicity

Posttranslational modification of proteins by attachment of small ubiquitin-related modifier (SUMO) contributes to numerous cellular phenomena. Sumoylation sometimes creates and abolishes binding interfaces, but increasing evidence points to another role for sumoylation in promoting the solubility o...

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Autores principales: Krumova, Petranka, Meulmeester, Erik, Garrido, Manuel, Tirard, Marilyn, Hsiao, He-Hsuan, Bossis, Guillaume, Urlaub, Henning, Zweckstetter, Markus, Kügler, Sebastian, Melchior, Frauke, Bähr, Mathias, Weishaupt, Jochen H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135405/
https://www.ncbi.nlm.nih.gov/pubmed/21746851
http://dx.doi.org/10.1083/jcb.201010117
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author Krumova, Petranka
Meulmeester, Erik
Garrido, Manuel
Tirard, Marilyn
Hsiao, He-Hsuan
Bossis, Guillaume
Urlaub, Henning
Zweckstetter, Markus
Kügler, Sebastian
Melchior, Frauke
Bähr, Mathias
Weishaupt, Jochen H.
author_facet Krumova, Petranka
Meulmeester, Erik
Garrido, Manuel
Tirard, Marilyn
Hsiao, He-Hsuan
Bossis, Guillaume
Urlaub, Henning
Zweckstetter, Markus
Kügler, Sebastian
Melchior, Frauke
Bähr, Mathias
Weishaupt, Jochen H.
author_sort Krumova, Petranka
collection PubMed
description Posttranslational modification of proteins by attachment of small ubiquitin-related modifier (SUMO) contributes to numerous cellular phenomena. Sumoylation sometimes creates and abolishes binding interfaces, but increasing evidence points to another role for sumoylation in promoting the solubility of aggregation-prone proteins. Using purified α-synuclein, an aggregation-prone protein implicated in Parkinson’s disease that was previously reported to be sumoylated upon overexpression, we compared the aggregation kinetics of unmodified and modified α-synuclein. Whereas unmodified α-synuclein formed fibrils, modified α-synuclein remained soluble. The presence of as little as 10% sumoylated α-synuclein was sufficient to delay aggregation significantly in vitro. We mapped SUMO acceptor sites in α-synuclein and showed that simultaneous mutation of lysines 96 and 102 to arginine significantly impaired α-synuclein sumoylation in vitro and in cells. Importantly, this double mutant showed increased propensity for aggregation and cytotoxicity in a cell-based assay and increased cytotoxicity in dopaminergic neurons of the substantia nigra in vivo. These findings strongly support the model that sumoylation promotes protein solubility and suggest that defects in sumoylation may contribute to aggregation-induced diseases.
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spelling pubmed-31354052012-01-11 Sumoylation inhibits α-synuclein aggregation and toxicity Krumova, Petranka Meulmeester, Erik Garrido, Manuel Tirard, Marilyn Hsiao, He-Hsuan Bossis, Guillaume Urlaub, Henning Zweckstetter, Markus Kügler, Sebastian Melchior, Frauke Bähr, Mathias Weishaupt, Jochen H. J Cell Biol Research Articles Posttranslational modification of proteins by attachment of small ubiquitin-related modifier (SUMO) contributes to numerous cellular phenomena. Sumoylation sometimes creates and abolishes binding interfaces, but increasing evidence points to another role for sumoylation in promoting the solubility of aggregation-prone proteins. Using purified α-synuclein, an aggregation-prone protein implicated in Parkinson’s disease that was previously reported to be sumoylated upon overexpression, we compared the aggregation kinetics of unmodified and modified α-synuclein. Whereas unmodified α-synuclein formed fibrils, modified α-synuclein remained soluble. The presence of as little as 10% sumoylated α-synuclein was sufficient to delay aggregation significantly in vitro. We mapped SUMO acceptor sites in α-synuclein and showed that simultaneous mutation of lysines 96 and 102 to arginine significantly impaired α-synuclein sumoylation in vitro and in cells. Importantly, this double mutant showed increased propensity for aggregation and cytotoxicity in a cell-based assay and increased cytotoxicity in dopaminergic neurons of the substantia nigra in vivo. These findings strongly support the model that sumoylation promotes protein solubility and suggest that defects in sumoylation may contribute to aggregation-induced diseases. The Rockefeller University Press 2011-07-11 /pmc/articles/PMC3135405/ /pubmed/21746851 http://dx.doi.org/10.1083/jcb.201010117 Text en © 2011 Krumova et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Krumova, Petranka
Meulmeester, Erik
Garrido, Manuel
Tirard, Marilyn
Hsiao, He-Hsuan
Bossis, Guillaume
Urlaub, Henning
Zweckstetter, Markus
Kügler, Sebastian
Melchior, Frauke
Bähr, Mathias
Weishaupt, Jochen H.
Sumoylation inhibits α-synuclein aggregation and toxicity
title Sumoylation inhibits α-synuclein aggregation and toxicity
title_full Sumoylation inhibits α-synuclein aggregation and toxicity
title_fullStr Sumoylation inhibits α-synuclein aggregation and toxicity
title_full_unstemmed Sumoylation inhibits α-synuclein aggregation and toxicity
title_short Sumoylation inhibits α-synuclein aggregation and toxicity
title_sort sumoylation inhibits α-synuclein aggregation and toxicity
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135405/
https://www.ncbi.nlm.nih.gov/pubmed/21746851
http://dx.doi.org/10.1083/jcb.201010117
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