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First published online 30 January 2007
doi: 10.1242/jcs.03351

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Characterization of the proteasome interaction with the Sec61 channel in the endoplasmic reticulum

¹ University of Cambridge, Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Hills Road, Cambridge, CB2 2XY, UK
² Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

^* Author for correspondence (e-mail: kbr20{at}cam.ac.uk)

Accepted 17 November 2006

Biogenesis of secretory proteins requires their translocation into the endoplasmic reticulum (ER) through the Sec61 channel. Proteins that fail to fold are transported back into the cytosol and are degraded by proteasomes. For many substrates this retrograde transport is affected by mutations in the Sec61 channel, and can be promoted by ATP and the 19S regulatory particle of the proteasome, which binds directly to the Sec61 channel via its base. Here, we identify mutations in SEC61 which reduce proteasome binding to the channel, and demonstrate that proteasomes and ribosomes bind differently to cytosolic domains of the channel. We found that Sec63p and BiP coprecipitate with ER-associated proteasomes, but Sec63p does not contribute to proteasome binding to the ER. The 19S base contains six AAA-ATPase subunits (Rpt proteins) that have non-equivalent functions in proteasome-mediated protein turnover and form a hetero-hexamer. Mutations in the ATP-binding sites of individual Rpt proteins all reduced the affinity of 19S complexes for the ER, suggesting that the 19S base in the ATP-bound conformation docks at the Sec61 channel.

Key words: ER translocation, ER quality control, ERAD, 19S regulatory particle, Rpt proteins, Yeast, Ribosome binding

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