Fig. 6.

R179H 3D model and mechanism of action in ARCD. a. Ribbon 3D representation of monomeric α1-actin oriented to view the interstrand surface shows the 4 actin subdomains (SD), the ADP/ATP-binding site, and the positioning of R179 and R258 on the interstrand surface. b. Surface projection of ARCD mutations to the same surface as R179 suggests similar mechanisms of actin polymerization disruption. c. Diagram of monomeric G-actin polymerization into double-stranded F-actin. d. Surface representation shows projection of the R179 side chain to the interstrand surface (left panel). Also represented are residues involved in interstrand contact: R179 and L112 (in gold) from one actin subunit contact K193 and T196 (in green) from the paired subunit, as schematized in the cartoon. The contact interface is altered by mutation to H179 (right panel). e. Pathogenesis model of ARCD. F-actin polymerization from a pool of wild-type (blue) and mutant (red) monomers results in variably defective filaments depending on the mutant:wild-type monomer ratio and the relative mutant monomer positioning into the F-actin chain. Blue arrows indicate compensatory mechanisms and red dotted arrows possible intrinsic phenotypes of SMCs with mutant ACTA2