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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.

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