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J. Biol. Chem., Vol. 283, Issue 1, 294-300, January 4, 2008

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V-ATPase V₀ Sector Subunit a1 in Neurons Is a Target of Calmodulin^*

Wei Zhang, Dong Wang, Elzi Volk, Hugo J. Bellen^¶1, Peter Robin Hiesinger², and Florante A. Quiocho³

From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology, ^¶Departments of Molecular and Human Genetics and Neuroscience and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030 and the Department of Physiology and Green Center Division for Systems Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The V₀ complex forms the proteolipid pore of a vesicular ATPase that acidifies vesicles. In addition, an independent function in membrane fusion has been suggested in vacuolar fusion in yeast and synaptic vesicle exocytosis in fly neurons. Evidence for a direct role in secretion has also recently been presented in mouse and worm. The molecular mechanisms of how the V₀ components might act or are regulated are largely unknown. Here we report the identification and characterization of a calmodulin-binding site in the large cytosolic N-terminal region of the Drosophila protein V100, the neuron-specific V₀ subunit a1. V100 forms a tight complex with calmodulin in a Ca²⁺-dependent manner. Mutations in the calmodulin-binding site in Drosophila lead to a loss of calmodulin recruitment to synapses. Neuronal expression of a calmodulin-binding deficient V100 uncovers an incomplete rescue at low levels and cellular toxicity at high levels. Our results suggest a vesicular ATPase V₀-dependent function of calmodulin at synapses.

Received for publication, September 26, 2007 , and in revised form, October 10, 2007.

^* This work was supported by the Welch Foundation (Grants Q581 to F. A. Q. and I-1657 to P. R. H.) and Eugene McDermott Endowed Scholarship (to P. R. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1 and S2.

¹ An investigator of the Howard Hughes Medical Institute.

² To whom correspondence may be addressed. Tel.: 214-645-6060; Fax: 214-645-6049; E-mail: robin.hiesinger{at}utsouthwestern.edu. ³ To whom correspondence may be addressed. Tel.: 713-798-6565; Fax: 713-798-8516; E-mail: faq{at}bcm.tmc.edu.

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