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J Biol Chem, Vol. 274, Issue 53, 37743-37749, December 31, 1999

Rapid Degradation of an Abnormal Protein in Escherichia coli Proceeds through Repeated Cycles of Association with GroEL^*

Olga Kandror, Michael Sherman, and Alfred Goldberg

From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Molecular chaperones are necessary for the breakdown of many abnormal proteins, but their functions in this process have remained obscure. The rapid degradation of the abnormal fusion protein CRAG in Escherichia coli requires the molecular chaperones GroEL, GroES, and trigger factor and proceeds through the formation of a CRAG-GroEL-trigger factor complex. Also associated with GroEL are smaller discrete fragments of CRAG. Pulse-chase experiments showed that these fragments were short-lived intermediates in CRAG degradation formed by C-terminal cleavages. Thus, CRAG degradation is not highly processive. In cells lacking the ClpP protease, the generation of these fragments and their subsequent degradation were much slower than in the wild type. Dissociation of CRAG from GroEL was necessary for its digestion by the ClpP protease, because in a groES temperature-sensitive mutant, CRAG was stable and accumulated on GroEL. Furthermore, the expression of a dominant GroEL mutant defective in substrate dissociation slowed degradation of both CRAG and the fragments. Therefore, we suggest that CRAG degradation proceeds through multiple rounds of substrate binding to GroEL, followed by their GroES-dependent dissociation, which allows further digestion by the protease. In this multistep process, GroEL and GroES function repeatedly, apparently to allow further degradation of CRAG and its fragments by the protease.

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^* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Boston Biomedical, Research Inst., Boston, MA 02114.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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