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J. Biol. Chem., Vol. 279, Issue 15, 15289-15297, April 9, 2004

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Degradation of Mutated Bovine Pancreatic Trypsin Inhibitor in the Yeast Vacuole Suggests Post-endoplasmic Reticulum Protein Quality Control^*

Christina M. Coughlan¶, Jennifer L. Walker, Jared C. Cochran, K. Dane Wittrup||, and Jeffrey L. Brodsky**

From the Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, the ^||Department of Chemical Engineering and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and the ^¶Department of Biological Sciences, University of Denver, Denver, Colorado 80208

The rate-limiting step in protein secretion is folding, which occurs in the endoplasmic reticulum (ER) lumen, and almost all secreted proteins contain disulfide bonds that form in the ER and stabilize the native state. Secreted proteins unable to fold may aggregate or they may be subject to ER-associated protein degradation. To examine the fate of aberrant forms of a well characterized, disulfide-bonded secreted protein, we expressed bovine pancreatic trypsin inhibitor in yeast. Bovine pancreatic trypsin inhibitor is a single domain, 58-amino acid polypeptide containing three disulfide bonds, and yeast cells secrete the wild type protein. In contrast, the Y35L mutant, which folds rapidly but is unstable, remains soluble and is not secreted. Surprisingly, the proteolysis of Y35L is unaffected in yeast containing mutations in genes encoding factors required for ER-associated protein degradation and is stable if artificially retained in the ER. Rather, Y35L is diverted from the Golgi to the vacuole and degraded. Because only the mutant protein is quantitatively proteolyzed these data suggest that a post-ER quality control check-point diverts unstable proteins to the vacuole for degradation.

Received for publication, September 2, 2003 , and in revised form, January 21, 2004.

^* This work was supported in part by National Science Foundation Grant MCB-0110331 (to J. L. 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.

Supported by a postdoctoral fellowship from the American Heart Association.

^** To whom correspondence should be addressed: 274 Crawford Hall, Dept. of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260. Tel.: 412-624-4831; Fax: 412-624-4759; E-mail: jbrodsky{at}pitt.edu.

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