Structural analysis of Ca(2+)-binding pocket of synaptotagmin 5 C2A domain.

Synaptotagmins constitute a family of multifunctional integral membrane proteins found predominantly on vesicles in neural and endocrine tissues. 17 isoforms of synaptotagmin family in mammals have been identified, 7 isoforms among them are known to be able to bind Ca(2+) via their C2 domains. This study presents the crystal structure of the first C2 domain (C2A domain) of synaptotagmin 5 complexed with Ca(2+) at 1.90Å resolution. Comparison of the Ca(2+)-binding pocket of synaptotagmin 5 C2A domain with other synaptotagmin C2 domains demonstrated that a serine residue locating at Ca(2+)-binding loop probably responsible to the conformational variation of Ca(2+)-binding pocket, and thus impacts the Ca(2+)-binding mechanism of C2 domain, which is verified by structural analysis of the serine mutant and Ca(2+)-binding assays via isothermal titration calorimetry. Alteration of Ca(2+)-binding mechanism might be correlated with different Ca(2+) response rates of synaptotagmins, which is the basis of the functions of synaptotagmins in regulating various types of Ca(2+)-triggered vesicle-membrane fusion processes.

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