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J. Biol. Chem., Vol. 278, Issue 38, 35903-35913, September 19, 2003

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Use of Modular Substrates Demonstrates Mechanistic Diversity and Reveals Differences in Chaperone Requirement of ERAD^*

Christof Taxis , Reiner Hitt, Sae-Hun Park, Peter M. Deak , Zlatka Kostova and Dieter H. Wolf ¶

From the Institut für Biochemie, Universität Stuttgart, 70569 Stuttgart, Germany

The endoplasmic reticulum (ER) harbors a protein quality control system, which monitors protein folding in the ER. Elimination of malfolded proteins is an important function of this protein quality control. Earlier studies with various soluble and transmembrane ER-associated degradation (ERAD) substrates revealed differences in the ER degradation machinery used. To unravel the nature of these differences we generated two type I membrane ERAD substrates carrying malfolded carboxypeptidase yscY (CPY^*) as the ER-luminal ERAD recognition motif. Whereas the first, CT^* (CPY^*-TM), has no cytoplasmic domain, the second, CTG^*, has the green fluorescent protein present in the cytosol. Together with CPY^*, these three substrates represent topologically diverse malfolded proteins, degraded via ERAD. Our data show that degradation of all three proteins is dependent on the ubiquitin-proteasome system involving the ubiquitin-protein ligase complex Der3/Hrd1p-Hrd3p, the ubiquitin conjugating enzymes Ubc1p and Ubc7p, as well as the AAA-ATPase complex Cdc48-Ufd1-Npl4 and the 26S proteasome. In contrast to soluble CPY^*, degradation of the membrane proteins CT^* and CTG^* does not require the ER proteins Kar2p (BiP) and Der1p. Instead, CTG^* degradation requires cytosolic Hsp70, Hsp40, and Hsp104p chaperones.

Received for publication, January 31, 2003 , and in revised form, June 23, 2003.

^* This work was supported by the Deutsche Forschungsgemeinschaft, Bonn, the German Federal Ministry of Education and Research within the framework of the German-Israeli Project Cooperation (DIP), Bonn, and the Fonds der Chemischen Industrie. 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.

Current address: European Molecular Biology Laboratory, Meyerhofstr. 1, 69117 Heidelberg, Germany.

Current address: Fachgruppe Biotechnologie, Universität Hohenheim, Emil-Wolff-Str. 14, 70599 Stuttgart, Germany.

^¶ To whom correspondence should be addressed: Institut für Biochemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany. Tel.: 49-711-685-4390; Fax: 49-711-685-4392; E-mail: dieter.wolf{at}po.uni-stuttgart.de.

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