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J. Biol. Chem., Vol. 283, Issue 28, 19521-19529, July 11, 2008

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Roles of the Glycogen-binding Domain and Snf4 in Glucose Inhibition of SNF1 Protein Kinase^*

Milica Momcilovic¹, Surtaj H. Iram¹, Yang Liu, and Marian Carlson²

From the Departments of Biochemistry and Molecular Biophysics and Genetics and Development and Microbiology, Columbia University, New York, New York 10032

The SNF1/AMP-activated protein kinase (AMPK) family is required for adaptation to metabolic stress and energy homeostasis. The subunit of AMPK binds AMP and ATP, and mutations that affect binding cause human disease. We have here addressed the role of the Snf4 () subunit in regulating SNF1 protein kinase in response to glucose availability in Saccharomyces cerevisiae. Previous studies of mutant cells lacking Snf4 suggested that Snf4 counteracts autoinhibition by the C-terminal sequence of the Snf1 catalytic subunit but is dispensable for glucose regulation, and AMP does not activate SNF1 in vitro. We first introduced substitutions at sites that, in AMPK, contribute to nucleotide binding and regulation. Mutations at several sites relieved glucose inhibition of SNF1, as judged by catalytic activity, phosphorylation of the activation-loop Thr-210, and growth assays, although analogs of the severe human mutations R531G/Q had little effect. We further showed that alterations of Snf4 residues that interact with the glycogen-binding domain (GBD) of the β subunit strongly relieved glucose inhibition. Finally, substitutions in the GBD of the Gal83 β subunit that are predicted to disrupt interactions with Snf4 and also complete deletion of the GBD similarly relieved glucose inhibition of SNF1. Analysis of mutant cells lacking glycogen synthase showed that regulation of SNF1 is normal in the absence of glycogen. These findings reveal novel roles for Snf4 and the GBD in regulation of SNF1.

Received for publication, May 12, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM34095 (to M. C.). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: 701 W. 168th St., HSC922, New York, NY 10032. Tel.: 212-305-6314; Fax: 212-305-1741; E-mail: mbc1{at}columbia.edu.

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