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J. Biol. Chem., Vol. 282, Issue 22, 16117-16125, June 1, 2007

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A Conserved Sequence Immediately N-terminal to the Bateman Domains in AMP-activated Protein Kinase Subunits Is Required for the Interaction with the Subunits^*

Rosa Viana, Mhairi C. Towler, David A. Pan, David Carling^¶, Benoit Viollet^||**, D. Grahame Hardie, and Pascual Sanz¹

From the Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Jaime Roig 11, 46010 Valencia, Spain, and Centro de Investigación Biomédica en Red de Enfermedades Raras-Instituto de SaIud Carlos III, 46010 Valencia, Spain, the ^¶Cellular Stress Group, Medical Research Centre Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Crane Road, London W12 0NN, United Kingdom, the Division of Molecular Physiology, College of Life Sciences, University of Dundee, Sir James Black Centre, Dow Street, Dundee DD1 5EH, Scotland, the ^||Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France, and the ^**INSERM U567, 75014 Paris, France

Mammalian AMP-activated protein kinase is a serine/threonine protein kinase that acts as a sensor of cellular energy status. AMP-activated protein kinase is a heterotrimer of three different subunits, i.e. , , and , with being the catalytic subunit and and having regulatory roles. Although several studies have defined different domains in and involved in the interaction with the other subunits of the complex, little is known about the regions of the subunits involved in these interactions. To study this, we have made sequential deletions from the N termini of the subunit isoforms and studied the interactions with and subunits, both by two-hybrid analysis and by co-immunoprecipitation. Our results suggest that a conserved region of 20–25 amino acids in 1, 2, and 3, immediately N-terminal to the Bateman domains, is required for the formation of a functional, active complex. This region is required for the interaction with the subunits. The interaction between the and subunits does not require this region and occurs instead within the Bateman domains of the subunit, although the - interaction does appear to stabilize the - interaction. In addition, sequential deletions from the C termini of the subunits indicate that deletion of any of the CBS (cystathionine -synthase) motifs prevents the formation of a functional complex with the and subunits.

Received for publication, December 26, 2006 , and in revised form, March 21, 2007.

Addendum—At the time that the manuscript was under revision, Townley and Shapiro (41) have defined the crystal structure of the AMPK complex from the yeast S. pombe. They demonstrate that the and subunits interact directly and that the pre-CBS1 sequence of the subunit participates in the binding to the subunit.

^* This work was supported by the EXGENESIS Integrated Project (Grant LSHM-CT-2004-005272) funded by the European Commission, by the Spanish Ministry of Education and Science (Grant SAF2005-00852 to P. S.), and by a Programme Grant from the Wellcome Trust (to D. G. 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.

¹ To whom correspondence should be addressed. Tel.: 3496-339-1779; Fax: 3496-369-0800; E-mail: sanz{at}ibv.csic.es.

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