Prediction and Analysis of the Widely-Varying Association Rates of Actin-Binding Proteins

Abstract

Actin is an abundant component of the eukaryotic cell. It forms the cytoskeleton, the backbone of the cell. Actin polymerization and depolymerization are controlled by a class of proteins called actin-binding proteins. Their functions range from increasing the rate of actin polymerization, to trapping actin in 1:1 complexes. The widely-varying rates of the actin-binding proteins associating with actin, from 2.1 × 104 to 2.4 × 107 M−1s−1, likely play essential roles in regulating actin polymerization and depolymerization. Previously we have developed a transient-complex theory for computing protein association mechanisms and association rates [1]. The transient complex is an intermediate in which the two associating proteins have near-native separation and relative orientation but have yet to form short-range specific interactions of the native complex. The association rate constant is predicted as ka = ka0e-ΔGel∗/kBT, where ka0 is the basal rate constant for reaching the transient complex by random diffusion, and the Boltzmann factor captures the rate enhancement by long-range electrostatic attraction. Here we applied the transient-complex theory to study the association of seven actin-binding proteins with actin. We found that the 1000-fold variations of ka among the actin-binding proteins arose mostly from disparate electrostatic contributions. There basal rates also showed some variations, resulting from the different shapes of the interfaces formed by the seven actin-binding proteins with actin. This study lays the foundation for using association rate constants in regulating crucial cellular processes.[1] R. Alsallaq and H.-X. Zhou (2008). Electrostatic rate enhancement and transient complex of protein-protein association. Proteins 71, 320-335.