The top loops of the C2 domains from synaptotagmin and phospholipase A2 control functional specificity

The phospholipid-binding specificities of C-2 domains, widely distributed Ca2+-binding modules, differ greatly despite similar three-dimensional structures. To understand the molecular basis for this specificity, we have examined the synaptotagmin 1 C(2)A domain, which interacts in a primarily electrostatic, Ca2+-dependent reaction with negatively charged phospholipids, and the cytosolic phospholipase A(2) (cPLA(2)) C-2 domain, which interacts by a primarily hydrophobic Ca2+-dependent mechanism with neutral phospholipids. We show that grafting the short Ca2+-binding loops from the tip of the cPLA(2) C-2 domain onto the top of the synaptotagmin I C(2)A domain confers onto the synaptotagmin I C(2)A domain the phospholipid binding specificity of the cPLA(2) C-2 domain, indicating that the functional specificity of C-2 domains is determined by their short top loops.