ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity for aggregation

Scientific Reports
Mahmoud KiaeiKottayil I Varughese

Abstract

Profilin-1 (PFN1) is a 140-amino-acid protein with two distinct binding sites-one for actin and one for poly-L-proline (PLP). The best-described function of PFN1 is to catalyze actin elongation and polymerization. Thus far, eight DNA mutations in the PFN1 gene encoding the PFN1 protein are associated with human amyotrophic lateral sclerosis (ALS). We and others recently showed that two of these mutations (Gly118Val or G118V and Cys71Gly or C71G) cause ALS in rodents. In vitro studies suggested that Met114Thr and Thr109Met cause the protein to behave abnormally and cause neurotoxicity. The mechanism by which a single amino acid change in human PFN1 causes the degeneration of motor neurons is not known. In this study, we investigated the structural perturbations of PFN1 caused by each ALS-associated mutation. We used molecular dynamics simulations to assess how these mutations alter the secondary and tertiary structures of human PFN1. Herein, we present our in silico data and analysis on the effect of G118V and T109M mutations on PFN1 and its interactions with actin and PLP. The substitution of valine for glycine reduces the conformational flexibility of the loop region between the α-helix and β-strand and enhances the hydrophobi...Continue Reading

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Citations

Jan 8, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lisa Marie WalterPeter Claus
May 30, 2019·Frontiers in Neurology·Udaya Geetha VijayakumarStephanie Marie-Rose Duguez
Oct 28, 2019·Frontiers in Pharmacology·Hui Min YapMohd Roslan Sulaiman
Mar 22, 2021·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Kathryn Russo, Kristi A Wharton
Aug 3, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Josephine C Esposto, Sanela Martic

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Software Mentioned

Visual Molecular Dynamics ( VMD )
VMD
Pymol
GROMACS

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