Biophysical analysis of three novel profilin-1 variants associated with amyotrophic lateral sclerosis indicates a correlation between their aggregation propensity and the structural features of their globular state.
Profilin-1 is a small protein involved in actin-mediated cytoskeleton rearrangement. Recently, mutations of profilin-1 have been associated with familial amyotrophic lateral sclerosis. It was previously reported that pathogenic mutations of profilin-1 increase the aggregation propensity of this protein, leaving its function unaffected. However, it is not clear if the mutations act by decreasing the conformational stability or by promoting structural perturbations of the folded state of this protein. In this work we have purified three novel profilin-1 mutants that were recently discovered and have investigated their conformational stability, structural features and aggregation behaviour in vitro. Analysis of the data obtained with the three novel variants, and a global statistical analysis with all profilin-1 mutants so far characterised, indicate significant correlations between aggregation propensity and structural perturbations of the folded state, rather than its conformational stability, in this group of mutants.
Edoardo
0000-0002-3648-4399
E
Del Poggetto
Ludovica
L
Gori
Fabrizio
F
Chiti
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D006801:Humans; D009154:Mutation; D051304:Profilins / Q000737:chemistry* / Q000235:genetics*; D066329:Protein Aggregates / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding / Q000187:drug effects; D055550:Protein Stability; D014508:Urea / Q000494:pharmacology
C495738:PFN1 protein, human; D051304:Profilins; D066329:Protein Aggregates; D014508:Urea