C2-domains, structure and function of a universal Ca2+-binding domain.

A vast amount of protein sequence data accumulated over recent years has revealed that protein modules are widespread in nature. Many intracellular and extracellular proteins consist, in part or fully, of combinations of protein modules. C2-domains, together with SH2, PTB, PH, SH3, WW, and PDZ domains, are typical examples of intracellular protein modules. These modules form independently folding domains of 80–160 residues with characteristic binding properties; C2-domains bind Ca 21 and phospholipids, SH2 and PTB domains phosphotyrosine-containing sequences, PH domains phosphatidylinositol phosphates, SH3 and WW domains proline-rich sequences, and PDZ domains C-terminal sequences. C2-domains are unique among these modules because phospholipid binding to many C2-domains is regulated by Ca . For this reason, C2-domains are sometimes referred to as Ca -dependent lipid binding domains. However, C2-domains are not obligatory Ca and phospholipid-binding modules. C2-domains have diverged evolutionarily into Ca-dependent and Ca-independent forms that interact with multiple targets. Thus, although most C2-domains are probably Ca-binding domains, they represent a family of versatile protein modules with diverse functions. C2-domains comprise approximately 130 residues and were first identified in protein kinase C (1). Close to 100 C2-domain sequences are listed in the current data banks. Although reviews of several C2-domain proteins have been published (2–11), recent results on the structure and interactions of C2-domains by x-ray crystallography and NMR spectroscopy offer a new opportunity to rationalize the properties of C2-domains in structural terms. In this minireview, we will attempt to use this opportunity and correlate the functional properties of C2-domains with their structures.