Aggregation is a context-dependent constraint on protein evolution

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• dc.contributor.author Monti, Michele
• dc.contributor.author Armaos, Alexandros, 1989-
• dc.contributor.author Fantini, Marco
• dc.contributor.author Pastore, Annalisa
• dc.contributor.author Tartaglia, Gian Gaetano
• dc.date.accessioned 2021-11-30T07:17:06Z
• dc.date.available 2021-11-30T07:17:06Z
• dc.date.issued 2021
• dc.description.abstract Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution. In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed in E. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function. Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in the cell.
• dc.description.sponsorship The research leading to these results was supported by the Dementia Research Institute (REI 3556 and AlzUK) (ARUK-PG2019B-020), European Research Council (RIBOMYLOME 309545 and ASTRA 855923), the H2020 projects (IASIS 727658 and INFORE 25080), the Spanish Ministry of Economy and Competitiveness BFU 2017-86970-P as well as the collaboration with Peter St. George-Hyslop financed by the Wellcome Trust.
• dc.format.mimetype application/pdf
• dc.identifier.citation Monti M, Armaos A, Fantini M, Pastore A, Tartaglia GG. Aggregation is a context-dependent constraint on protein evolution. Front Mol Biosci. 2021;8:678115. DOI: 10.3389/fmolb.2021.678115
• dc.identifier.doi http://dx.doi.org/10.3389/fmolb.2021.678115
• dc.identifier.issn 2296-889X
• dc.identifier.uri http://hdl.handle.net/10230/49093
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Mol Biosci. 2021;8:678115
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/855923
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/727658
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86970-P
• dc.rights © 2021 Monti, Armaos, Fantini, Pastore and Tartaglia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cellular fitness
• dc.subject.keyword Computational model
• dc.subject.keyword Deep scanning
• dc.subject.keyword Evolution
• dc.subject.keyword Protein aggregation
• dc.title Aggregation is a context-dependent constraint on protein evolution
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion