COFILIN AND GELSOLIN SEGMENT-1 - MOLECULAR-DYNAMICS SIMULATION AND BIOCHEMICAL-ANALYSIS PREDICT A SIMILAR ACTIN-BINDING MODE

An understanding of the actin-depolymerizing function attributed to me mbers of the ADF/cofilin/destrin superfamily requires a structural mod el of these proteins in complex with actin. As a step toward defining actin-cofilin interactions, the complex of yeast cofilin with monomeri c actin was predicted, starting with the actin-gelsolin segment-1 bind ing mode recently suggested for the actin-destrin complex. After refin ement by molecular dynamics simulation, the structure of cofilin conve rged in a new binding mode that required only minimal changes induced in the actin-cofilin interface. The predicted complex exhibits strong interactions between the N termini of actin and cofilin, mediated by a salt bridge of cofilin Arg3 with actin Asp1. The forming of this salt bridge could be prevented by the phosphorylation of cofilin Ser4, whi ch is believed to inhibit cofilin depolymerization activity. Recent mu tagenesis studies, crosslinking experiments and peptide binding studie s are consistent with the predicted model of the actin-cofilin complex . The structural homology between cofilin and gelsolin segment-1 bindi ng to actin was confirmed experimentally by two types of competitive b inding assays. (C) 1998 Academic Press.