The mutational landscape of a prion-like domain

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Bolognesi, Benedetta
• dc.contributor.author Faure, Andre J.
• dc.contributor.author Seuma, Mireia
• dc.contributor.author Schmiedel, Jörn M.
• dc.contributor.author Tartaglia, Gian Gaetano
• dc.contributor.author Lehner, Ben, 1978-
• dc.date.accessioned 2020-04-03T07:28:44Z
• dc.date.available 2020-04-03T07:28:44Z
• dc.date.issued 2019
• dc.description.abstract Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.
• dc.description.sponsorship Work in B.L.’s lab was supported by a European Research Council (ERC) Consolidator grant (616434), the Spanish Ministry of Economy and Competitiveness (BFU2017-89488-P), the AXA Research Fund, the Bettencourt Schueller Foundation, and Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, SGR-831) G.G.T.’s lab was supported by the European Research Council (RIBOMYLOME_309545) and the Spanish Ministry of Economy and Competitiveness (BFU2014-55054-P and BFU2017-86970-P). We acknowledge support from the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017’, the EMBL Partnership, and the CERCA Program/Generalitat de Catalunya. We thank Pablo Baeza Centurión, Xavier Salvatella, Alexandros Armaos and Benjamin Lang for discussion and assistance and the Eisenberg lab for help with the ZipperDB analysis.
• dc.format.mimetype application/pdf
• dc.identifier.citation Bolognesi B, Faure AJ, Seuma M, Schmiedel JM, Tartaglia GG, Lehner B. The mutational landscape of a prion-like domain. Nat Commun. 2019; 10(1):4162. DOI: 10.1038/s41467-019-12101-z
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-019-12101-z
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/44156
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2019; 10(1):4162
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-55054-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86970-P
• dc.rights © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Computational biology and bioinformatics
• dc.subject.keyword Genomics
• dc.subject.keyword Mechanisms of disease
• dc.subject.keyword Neurodegeneration
• dc.subject.keyword Systems biology
• dc.title The mutational landscape of a prion-like domain
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion