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J. Biol. Chem., Vol. 281, Issue 42, 31885-31893, October 20, 2006

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A Model for the Proteolipid Ring and Bafilomycin/Concanamycin-binding Site in the Vacuolar ATPase of Neurospora crassa^*

Barry J. Bowman¹, Mary E. McCall, Robert Baertsch, and Emma Jean Bowman

From the Departments of Molecular, Cell, and Developmental Biology, and Biomolecular Engineering, University of California, Santa Cruz, California 95064

The vacuolar ATPase has been implicated in a variety of physiological processes in eukaryotic cells. Bafilomycin and concanamycin, highly potent and specific inhibitors of the vacuolar ATPase, have been widely used to investigate the enzyme. Derivatives have been developed as possible therapeutic drugs. We have used random mutagenesis and site-directed mutagenesis to identify 23 residues in the c subunit involved in binding these drugs. We generated a model for the structure of the ring of c subunits in Neurospora crassa by using data from the crystal structure of the homologous subunits of the bacterium Enterococcus hirae (Murata, T., Yamato, I., Kakinuma, Y., Leslie, A. G., and Walker, J. E. (2005) Science 308, 654-659). In the model 10 of the 11 mutation sites that confer the highest degree of resistance are closely clustered. They form a putative drug-binding pocket at the interface between helices 1 and 2 on one c subunit and helix 4 of the adjacent c subunit. The excellent fit of the N. crassa sequence to the E. hirae structure and the degree to which the structural model predicts the clustering of these residues suggest that the folding of the bacterial and eukaryotic polypeptides is very similar.

Received for publication, June 8, 2006 , and in revised form, July 26, 2006.

^* This work was supported by NCI/SAIC Contract 22XS013A from the National Institutes of Health, National Institutes of Health Grant GM058903, and a grant from the University of California Cancer Research Coordinating Committee. 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. Tel.: 831-459-2245; E-mail: bowman{at}biology.ucsc.edu.

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