Molecular mechanisms of S100‐target protein interactions

Abstract

S100 proteins have no known enzymatic activity and exert their intracellular effects via interaction with and regulation of the activity of other proteins, termed target proteins, in both a Ca²⁺‐dependent and Ca²⁺‐independent manner. Structural studies have identified the linker region between the two EF‐hand Ca²⁺ binding domains and the C‐terminus as Ca²⁺‐dependent target protein binding sites in several S100 family members. In fact, C‐terminal aromatic residues are obligatory for interaction of S100A1 with several of its Ca²⁺‐dependent target proteins. Pharmacological studies suggest the presence of additional Ca²⁺‐dependent binding motifs on some family members. A minimum of seven family members interact with and regulate the activity of aldolase A in a Ca²⁺‐independent manner. In the case of S100A1, Ca²⁺‐independent target protein interactions utilize a binding motif distinct from the C‐terminal Ca²⁺‐dependent target protein binding site. Several studies suggest that ionic interactions participate in the interaction of S100 family members with Ca²⁺‐independent target proteins. While some target proteins are activated by multiple family members, other target proteins exhibit family member‐specific activation, i.e., they are activated by a single family member. As predicted, family member specific interactions appear to be mediated by regions that exhibit the most divergence in amino acid sequence among family members, the linker or “hinge” region and the C terminus. Further specificity in S100‐target protein interactions may arise from the different biochemical/biophysical properties of the individual family members, including affinity for metal ions (Ca²⁺, Zn²⁺, and Cu²⁺), oligomerization properties, heterodimerization, post‐translational modifications, and lipid‐binding. Delineation of the structural motifs that mediate S100‐target protein interactions and determination of the in vivo relevance of these interactions are needed to fully understand the role of S100 proteins in normal and diseased cells. Microsc. Res. Tech. 60:552–559, 2003.