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Vol. 10, Issue 7, 2285-2295, July 1999

Functional and Biochemical Analysis of the C2 Domains of Synaptotagmin IV

David M. Thomas,^* Gregory D. Ferguson,^§ Harvey R. Herschman,^§ and Lisa A. Elferink^*¶

 ^*Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202; and  Molecular Biology Institute and Departments of  ^§Biological Chemistry and  Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095-1570

Synaptotagmins (Syts) are a family of vesicle proteins that have been implicated in both regulated neurosecretion and general membrane trafficking. Calcium-dependent interactions mediated through their C2 domains are proposed to contribute to the mechanism by which Syts trigger calcium-dependent neurotransmitter release. Syt IV is a novel member of the Syt family that is induced by cell depolarization and has a rapid rate of synthesis and a short half-life. Moreover, the C2A domain of Syt IV does not bind calcium. We have examined the biochemical and functional properties of the C2 domains of Syt IV. Consistent with its non-calcium binding properties, the C2A domain of Syt IV binds syntaxin isoforms in a calcium-independent manner. In neuroendocrine pheochromocytoma (PC12) cells, Syt IV colocalizes with Syt I in the tips of the neurites. Microinjection of the C2A domain reveals that calcium-independent interactions mediated through this domain of Syt IV inhibit calcium-mediated neurotransmitter release from PC12 cells. Conversely, the C2B domain of Syt IV contains calcium binding properties, which permit homo-oligomerization as well as hetero-oligomerization with Syt I. Our observation that different combinatorial interactions exist between Syt and syntaxin isoforms, coupled with the calcium stimulated hetero-oligomerization of Syt isoforms, suggests that the secretory machinery contains a vast repertoire of biochemical properties for sensing calcium and regulating neurotransmitter release accordingly.

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   These authors contributed equally to this work.
^¶   Corresponding author. E-mail address: laelferi{at}sun.science.wayne.edu.

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Molecular Biology of the Cell
Vol. 10, 2285-2295, July 1999
Copyright © 1999 by The American Society for Cell Biology

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