THE C2 DOMAIN CALCIUM-BINDING MOTIF - STRUCTURAL AND FUNCTIONAL DIVERSITY

The C2 domain is a Ca2+-binding motif of approximately 130 residues in length originally identified in the Ca2+ dependent isoforms of protei n kinase C. Single and multiple copies of C2 domains have been identif ied in a growing number of eukaryotic signalling proteins that interac t with cellular membranes and mediate a broad array of critical intrac ellular processes, including membrane trafficking, the generation of l ipid-second messengers, activation of GTPases, and the control of prot ein phosphorylation. As a group, C2 domains display the remarkable pro perty of binding a variety of different ligands and substrates, includ ing Ca2+, phospholipids, inositol polyphosphates, and intracellular pr oteins. Expanding this functional diversity is the fact that not all p roteins containing C2 domains are regulated by Ca2+, suggesting that s ome C2 domains may play a purely structural role or may have lost the ability to bind Ca2+. The present review summarizes the information cu rrently available regarding the structure and function of the C2 domai n and provides a novel sequence alignment of 65 C2 domain primary stru ctures. This alignment predicts that C2 domains form two distinct topo logical folds, illustrated by the recent crystal structures of C2 doma ins from synaptotagmin I and phosphoinositide-specific phospholipase C -delta 1, respectively. The alignment highlights residues that may be critical to the C2 domain fold or required for Ca2+ binding and regula tion.