ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization

• DOI: 10.1073/pnas.2024605118
• Publication Date: 2021-06-01T23:22:05Z
• Authors: Eric J. Schmidt; Salome Funes; Jeanne E. McKeon; Brittany R. Morgan; Sivakumar Boopathy; Lauren C. O’Connor; Osman Bilsel; Francesca Massi; Antoine Jégou; Daryl A. Bosco
• Keywords: Protein Conformation, alpha-Helical; 0301 basic medicine; 0303 health sciences; [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]; Amyotrophic Lateral Sclerosis; Formins; Neurodegenerative Diseases; Actins; Polymerization; Profilins; 03 medical and health sciences; Phenotype; Mutation; [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]; Animals; Humans; Mutant Proteins; Proteostasis Deficiencies; [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]; HeLa Cells

Significance Mutations in profilin-1 (PFN1), an actin-binding protein, cause amyotrophic lateral sclerosis (ALS) through an unknown mechanism. Here, we carried out a series of biophysical and cell biological analyses to investigate the effects of ALS-linked mutations on PFN1 function. We found that some moderately misfolded ALS-linked variants bind certain formin proteins with higher affinity and also promote enhanced formin-mediated actin polymerization. Mutation-induced flexibility within actin- and polyproline-binding regions of PFN1 may underlie these phenotypes. However, severe misfolding of PFN1 leads to loss of function with respect to formin-mediated actin polymerization. Our results indicate that ALS-linked PFN1 perturbs actin dynamics, but the mechanism by which this perturbation occurs appears dependent upon the thermodynamic stability of the mutant protein.