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Crit Rev Biochem Mol Biol. 2013 Mar-Apr;48(2):89-97. doi: 10.3109/10409238.2012.742856. Epub 2012 Dec 13.

The role of allostery in the ubiquitin-proteasome system.

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1
Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA.

Abstract

The ubiquitin-proteasome system (UPS) is involved in many cellular processes including protein degradation. Degradation of a protein via this system involves two successive steps: ubiquitination and degradation. Ubiquitination tags the target protein with ubiquitin-like proteins (UBLs), such as ubiquitin, small ubiquitin-like modifier (SUMO) and NEDD8, via a cascade involving three enzymes: activating enzyme E1, conjugating enzyme E2 and E3 ubiquitin ligases. The proteasomes recognize the UBL-tagged substrate proteins and degrade them. Accumulating evidence indicates that allostery is a central player in the regulation of ubiquitination, as well as deubiquitination and degradation. Here, we provide an overview of the key mechanistic roles played by allostery in all steps of these processes, and highlight allosteric drugs targeting them. Throughout the review, we emphasize the crucial mechanistic role played by linkers in allosterically controlling the UPS action by biasing the sampling of the conformational space, which facilitate the catalytic reactions of the ubiquitination and degradation. Finally, we propose that allostery may similarly play key roles in the regulation of molecular machines in the cell, and as such allosteric drugs can be expected to be increasingly exploited in therapeutic regimes.

PMID:
23234564
PMCID:
PMC3609921
DOI:
10.3109/10409238.2012.742856
[Indexed for MEDLINE]
Free PMC Article
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