SYNAPTOTAGMIN-SYNTAXIN INTERACTION - THE C-2 DOMAIN AS A CA2-DEPENDENT ELECTROSTATIC SWITCH()

Synaptotagmin I is a synaptic vesicle protein that is thought to act a s a Ca2+ sensor in neurotransmitter release. The first C-2 domain of s ynaptotagmin I (C(2)A domain) contains a bipartite Ca2+-binding motif and interacts in a Ca2+-dependent manner with syntaxin, a central comp onent of the membrane fusion complex. Analysis by nuclear magnetic res onance spectroscopy and site-directed mutagenesis shows that this inte raction is mediated by the cooperative action of basic residues surrou nding the Ca2+-binding sites of the C(2)A domain and is driven by a ch ange in the electrostatic potential of the C(2)A domain induced by Ca2 + binding. A model is proposed whereby synaptotagmin acts as an electr ostatic switch in Ca2+-triggered synaptic vesicle exocytosis, promotin g a structural rearrangement in the fusion machinery that is effected by its interaction with syntaxin.