C 2‐Domain Proteins Involved in Membrane Traffic

Abstract

C 2 ‐domains are the second‐most abundant Ca 2+ ‐binding modules in nature. Their most common activity is Ca 2+ ‐dependent phospholipid binding, but other types of interactions have been observed for these versatile protein modules. A variety of proteins involved in membrane traffic contain multiple C 2 ‐domains, which often appear as two tandem C 2 ‐domains as in the case of synaptotagmins and rabphilin. The structures of the C 2 ‐domains of these proteins consist of a conserved β‐sandwich, formed by two four‐stranded β‐sheets, with variable loops at the top and the bottom that sometimes contain α‐helices. Multiple Ca 2+ ‐ions bind in a tight cluster at the top loops, usually without inducing substantial conformational changes. Instead, electrostatic changes caused by Ca 2+ binding induce the Ca 2+ ‐dependent interactions of C 2 ‐domains, which can also be aided by hydrophobic interactions and partial coordination of Ca 2+ by the target molecules. Extensive analysis of the structure and Ca 2+ ‐binding properties of the two synaptotagmin 1 C 2 ‐domains has helped design genetic experiments that have strongly supported the notion that this protein acts as the major Ca 2+ sensor in neurotransmitter release. These studies have also suggested that Ca 2+ ‐dependent phospholipid binding underlies the function of synaptotagmin 1 in triggering release.