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J. Biol. Chem., Vol. 279, Issue 36, 37298-37303, September 3, 2004

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Active Solubilization and Refolding of Stable Protein Aggregates By Cooperative Unfolding Action of Individual Hsp70 Chaperones^*

Anat Ben-Zvi, Paolo De Los Rios, Giovanni Dietler¶, and Pierre Goloubinoff||

From the Départment de Biologie Moléculaire Végétale, Université de Lausanne, CH-1015 Lausanne, Switzerland, Laboratoire de Biophysique Statistique, ITP-SB, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland, and ^¶Laboratoire de Physique de la Matière Vivante, IPMC-SB, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland

Hsp70 is a central molecular chaperone that passively prevents protein aggregation and uses the energy of ATP hydrolysis to solubilize, translocate, and mediate the proper refolding of proteins in the cell. Yet, the molecular mechanism by which the active Hsp70 chaperone functions are achieved remains unclear. Here, we show that the bacterial Hsp70 (DnaK) can actively unfold misfolded structures in aggregated polypeptides, leading to gradual disaggregation. We found that the specific unfolding and disaggregation activities of individual DnaK molecules were optimal for large aggregates but dramatically decreased for small aggregates. The active unfolding of the smallest aggregates, leading to proper global refolding, required the cooperative action of several DnaK molecules per misfolded polypeptide. This finding suggests that the unique ATP-fueled locking/unlocking mechanism of the Hsp70 chaperones can recruit random chaperone motions to locally unfold misfolded structures and gradually disentangle stable aggregates into refoldable proteins.

Received for publication, May 20, 2004 , and in revised form, June 14, 2004.

^* This work was supported by Grant 31-65211.01 from the Swiss National Science Foundation. 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.

^|| To whom correspondence should be addressed. Tel.: 41-21-692-4232; Fax: 41-21-692-4195; E-mail: Pierre.Goloubinoff{at}ie-bpv.unil.ch.

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