CPI-Motif Regulators of Actin Capping Protein: Mechanisms and Functions

This review provides an in-depth account of the cellular and organismal functions, biochemical mechanisms, and pathological roles of a diverse group of proteins that share a conserved motif that binds to actin capping protein (CP). This CP-interacting (CPI) motif was defined by biochemical and structural studies; it contains several conserved residues necessary for high-affinity binding to CP. The motif has been found in a handful of otherwise unrelated proteins. Binding of a CPI motif to CP induces a conformational change that alters the binding surface on the opposite side of CP, which binds both the barbed end of the actin filament (“capping”) and V-1, a steric blocker of capping. This allosteric change has two effects. First, it decreases the affinity of CP for the barbed end, thereby inhibiting capping and promoting uncapping. Second, it activates CP by releasing it from its inactive, V-1-bound, sequestered state. These two effects appear to oppose each other in the cell. The review highlights the properties of CARMILs as CPI-motif proteins that also contain additional CP-binding and membrane-binding domains. Future directions for the field include understanding how the biochemical activities of individual CPI motifs contribute to the cellular functions of the proteins that contain them.