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1: J Biol Chem. 1998 Dec 4;273(49):32848-56.
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Endoplasmic reticulum degradation of a mutated ATP-binding cassette transporter Pdr5 proceeds in a concerted action of Sec61 and the proteasome.

Plemper RK, Egner R, Kuchler K, Wolf DH.

Institut für Biochemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany.

Degradation of misfolded or tightly regulated proteins in the endoplasmic reticulum (ER) is performed by the cytosolic ubiquitin-proteasome system and therefore requires their prior transport back to the cytosol. Here, we report on the extraction and degradation mechanism of a polytopic membrane protein. Rapid proteasomal degradation of a mutated form of the ATP-binding cassette transporter Pdr5 retained in the ER is initialized at the lumenal face of the ER membrane. Using different antibodies directed against the cytosolic tails or a lumenal loop of the transmembrane protein, it could be demonstrated that the turnover of Pdr5* demands the concerted action of both the Sec61 translocon and the ubiquitin-proteasome system. We observed a stabilization of the entire molecule within the ER membrane in yeast mutants characterized by a reduced translocation capacity or by functionally attenuated proteasomes. Moreover, no degradation intermediates were detected in any of the mutants that impede degradation of Pdr5*. Therefore, initial steps are rate-limiting for cleavage and mutations that impede downstream events prevent initiation of the process. Our data suggest that ER degradation is a mechanistically highly integrated process, requiring the combined operation of components of the degradation system acting at the lumenal face of the ER membrane, the Sec61 translocon, and the ubiquitin-proteasome system.

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PMID: 9830032 [PubMed - indexed for MEDLINE]