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J. Biol. Chem., Vol. 282, Issue 34, 24743-24751, August 24, 2007

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Cellular Environment Is Important in Controlling V-ATPase Dissociation and Its Dependence on Activity^*

From the Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111

One mechanism of regulating V-ATPase activity in vivo involves reversible dissociation into its component V₁ and V₀ domains, which in yeast occurs in response to glucose depletion. V-ATPase complexes containing the Vph1p isoform of subunit a (VCC) are targeted to the vacuole, and Stv1p-containing complexes (SCC) are targeted to the Golgi. Overexpression of Stv1p results in mistargeting of SCC to the vacuole. We have investigated the role of the a subunit isoform and cellular environment in controlling dissociation using vacuolar protein sorting (vps) mutants that accumulate proteins in either the prevacuolar compartment (PVC) (vps27) or a post-Golgi compartment (PGC) (vps21). Dissociation of both VCC and SCC depends upon cellular environment, with dissociation most complete in the vacuole and least complete in the PVC. The dependence of dissociation on V-ATPase activity was also investigated using both concanamycin and inactivating mutations. Concanamycin partly blocks dissociation of both VCC and SCC in all three compartments, with inhibition generally greater for SCC than VCC. The R735Q mutant of Vph1p results in loss of both ATPase and proton transport, whereas the R735K mutant lacks proton transport but has 10% of wild type ATPase activity. For VCC in the vacuole, dissociation is completely blocked for the R735Q but not the R735K mutant. Significant dissociation of VCC is observed for both mutants in the PVC and PGC, indicating that V-ATPase activity is not absolutely required for dissociation. Similar results were obtained for SCC, although dissociation of SCC is again generally more sensitive to activity than VCC. These results suggest that the cellular environment is important both in controlling in vivo dissociation of the V-ATPase and the dependence of this process on catalytic activity. Moreover, catalytic activity is not absolutely required for V-ATPase dissociation.

Received for publication, January 23, 2007 , and in revised form, May 9, 2007.

^* This work was supported by National Institutes of Health Grant GM 34478 (to M. F.). 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.

¹ To whom correspondence should be addressed: Dept. of Physiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Tel.: 617-636-6939; Fax: 617-636-0445; E-mail: michael.forgac{at}tufts.edu.

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