ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization
| Autor: | Daryl A. Bosco, Francesca Massi, Brittany R. Morgan, Eric J. Schmidt, Salome Funes, Antoine Jégou, Sivakumar Boopathy, Osman Bilsel, Lauren C. O’Connor, Jeanne E. McKeon |
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| Přispěvatelé: | Institut Jacques Monod (IJM (UMR_7592)), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP) |
| Rok vydání: | 2021 |
| Předmět: |
Protein Conformation
alpha-Helical Mutant Formins Context (language use) [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] macromolecular substances Polymerization Profilins 03 medical and health sciences 0302 clinical medicine Mutant protein Profilin-1 Animals Humans [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Proteostasis Deficiencies Actin 030304 developmental biology Polyproline helix 0303 health sciences Multidisciplinary [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] biology Chemistry Amyotrophic Lateral Sclerosis Neurodegenerative Diseases Biological Sciences Actins Cell biology Phenotype Mutation biology.protein Mutant Proteins Protein folding 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2021, 118 (23), pp.e2024605118. ⟨10.1073/pnas.2024605118⟩ |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2024605118 |
| Popis: | International audience; Profilin-1 (PFN1) plays important roles in modulating actin dynamics through binding both monomeric actin and proteins enriched with polyproline motifs. Mutations in PFN1 have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, whether ALS-linked mutations affect PFN1 function has remained unclear. To address this question, we employed an unbiased proteomics analysis in mammalian cells to identify proteins that differentially interact with mutant and wild-type (WT) PFN1. These studies uncovered differential binding between two ALS-linked PFN1 variants, G118V and M114T, and select formin proteins. Furthermore, both variants augmented formin-mediated actin assembly relative to PFN1 WT. Molecular dynamics simulations revealed mutation-induced changes in the internal dynamic couplings within an alpha helix of PFN1 that directly contacts both actin and polyproline, as well as structural fluctuations within the actin- and polyproline-binding regions of PFN1. These data indicate that ALS-PFN1 variants have the potential for heightened flexibility in the context of the ternary actin–PFN1–polyproline complex during actin assembly. Conversely, PFN1 C71G was more severely destabilized than the other PFN1 variants, resulting in reduced protein expression in both transfected and ALS patient lymphoblast cell lines. Moreover, this variant exhibited loss-of-function phenotypes in the context of actin assembly. Perturbations in actin dynamics and assembly can therefore result from ALS-linked mutations in PFN1. However, ALS-PFN1 variants may dysregulate actin polymerization through different mechanisms that depend upon the solubility and stability of the mutant protein. |
| Databáze: | OpenAIRE |
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