Article
- The EMBO Journal (2009) 28, 1867 - 1877
- doi:10.1038/emboj.2009.115
Published online: 23 April 2009
There is a Have you seen ...? (July 2009) associated with this Article.
Subject Category:
S5a promotes protein degradation by blocking synthesis of nondegradable forked ubiquitin chains
Hyoung Tae Kim1, Kwang Pyo Kim1,2,3, Tomoaki Uchiki1, Steven P Gygi1,2 and Alfred L Goldberg1
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- Taplin Biological Mass Spectrometry Facility, Harvard Medical School, Boston, MA, USA
- Department of Molecular Biotechnology, Institution of Biomedical Science and Technology, Konkuk University, Seoul, Korea
Correspondence to:
Alfred L Goldberg, Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. Tel.: +1 617 432 1855; Fax: +1 617 232 0173; E-mail: Alfred_Goldberg@hms.harvard.edu
Received 11 November 2008; Accepted 26 March 2009
Abstract
Ubiquitin (Ub)–protein conjugates formed by purified ring-finger or U-box E3s with the E2, UbcH5, resist degradation and disassembly by 26S proteasomes. These chains contain multiple types of Ub forks in which two Ub's are linked to adjacent lysines on the proximal Ub. We tested whether cells contain factors that prevent formation of nondegradable conjugates and whether the forked chains prevent proteasomal degradation. S5a is a ubiquitin interacting motif (UIM) protein present in the cytosol and in the 26S proteasome. Addition of S5a or a GST-fusion of S5a's UIM domains to a ubiquitination reaction containing 26S proteasomes, UbcH5, an E3 (MuRF1 or CHIP), and a protein substrate, dramatically stimulated its degradation, provided S5a was present during ubiquitination. Mass spectrometry showed that S5a and GST–UIM prevented the formation of Ub forks without affecting synthesis of standard isopeptide linkages. The forked Ub chains bind poorly to 26S proteasomes unlike those synthesized with S5a present or linked to Lys63 or Lys48 chains. Thus, S5a (and presumably certain other UIM proteins) function with certain E3/E2 pairs to ensure synthesis of efficiently degraded non-forked Ub conjugates.
Keywords:
- nondegradable forked ubiquitin chain,
- proteasome,
- Rpn10,
- S5a
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