Dynamical features of smooth muscle actin pathological mutants: The arginine-257(258)-Cysteine cases

Abstract

The R257(8)C mutation in smooth muscle actins, ACTG2 and ACTA2, is the most frequent cause of severe genetic diseases: namely, visceral myopathy, and familial thoracic aortic aneurysms and dissections, which respectively, stem from impairment of the visceral and vascular muscle. The molecular mechanisms underlying such pathologies are not fully elucidated. In the absence of experimental data of WT and mutated actins in their monomeric (g-) and filamentous (f-) form, molecular dynamics can shed light on the role of the R257(8)C in protein structure and dynamics. Analysis of g-actins does not show significant differences between WT and mutated proteins suggesting the correct monomers folding. On the contrary, mutated filaments are destabilized. Subunits of R257C f-ACTG2 adopt non optimal angles and in R258C f-ACTA2 we observe depolymerization already in the simulated time frame. Overall, our data points to a crucial role of residue R257(8) in actin structure and dynamics, in particular when the protein assembles into the filament.