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J. Biol. Chem., Vol. 281, Issue 11, 7012-7021, March 17, 2006

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PhLP3 Modulates CCT-mediated Actin and Tubulin Folding via Ternary Complexes with Substrates^*

Peter C. Stirling¹, Jorge Cuéllar, Gabriel A. Alfaro, Fatima El Khadali^¶, Christopher T. Beh, José M. Valpuesta, Ronald Melki^¶, and Michel R. Leroux²

From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Campus de la Universidad Autónoma de Madrid, 28049 Madrid, Spain, and ^¶Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, 91198 Gif-sur-Yvette Cedex, France

Many ATP-dependent molecular chaperones, including Hsp70, Hsp90, and the chaperonins GroEL/Hsp60, require cofactor proteins to regulate their ATPase activities and thus folding functions in vivo. One conspicuous exception has been the eukaryotic chaperonin CCT, for which no regulator of its ATPase activity, other than non-native substrate proteins, is known. We identify the evolutionarily conserved PhLP3 (phosducin-like protein 3) as a modulator of CCT function in vitro and in vivo. PhLP3 binds CCT, spanning the cylindrical chaperonin cavity and contacting at least two subunits. When present in a ternary complex with CCT and an actin or tubulin substrate, PhLP3 significantly diminishes the chaperonin ATPase activity, and accordingly, excess PhLP3 perturbs actin or tubulin folding in vitro. Most interestingly, however, the Saccharomyces cerevisiae PhLP3 homologue is required for proper actin and tubulin function. This cellular role of PhLP3 is most apparent in a strain that also lacks prefoldin, a chaperone that facilitates CCT-mediated actin and tubulin folding. We propose that the antagonistic actions of PhLP3 and prefoldin serve to modulate CCT activity and play a key role in establishing a functional cytoskeleton in vivo.

Received for publication, December 12, 2005 , and in revised form, January 6, 2006.

^* This work was supported in part by the Canadian Institutes of Health Research Grant BMA121093 (to M. R. L.), the Association pour la Recherche sur le Cancer grant (to R. M.), BFU2004-00232/BMC Grant from the Spanish Ministry of Education (to J. M. V.), and a Science and a Natural Sciences and Engineering Research Council of Canada discovery grant (to C. T. B.). 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 Supported by scholarships from Natural Sciences and Engineering Research Council of Canada and the Michael Smith Foundation for Health Research.

² Recipient of scholar awards from the Michael Smith Foundation for Health Research and Canadian Institutes of Health Research. To whom correspondence should be addressed. Tel.: 604-268-6683; Fax: 604-268-5583; E-mail: leroux{at}sfu.ca.

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