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J Biol Chem. 2011 Jan 7;286(1):607-19. doi: 10.1074/jbc.M110.153122. Epub 2010 Oct 14.

Docking-dependent ubiquitination of the interferon regulatory factor-1 tumor suppressor protein by the ubiquitin ligase CHIP.

Author information

1
CRUK Interferon and Cell Signalling Group, Cell Signalling Unit, Institute of Genetics and Molecular Medicine, Crewe Road South, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom.

Abstract

Characteristically for a regulatory protein, the IRF-1 tumor suppressor turns over rapidly with a half-life of between 20-40 min. This allows IRF-1 to reach new steady state protein levels swiftly in response to changing environmental conditions. Whereas CHIP (C terminus of Hsc70-interacting protein), appears to chaperone IRF-1 in unstressed cells, formation of a stable IRF-1·CHIP complex is seen under specific stress conditions. Complex formation, in heat- or heavy metal-treated cells, is accompanied by a decrease in IRF-1 steady state levels and an increase in IRF-1 ubiquitination. CHIP binds directly to an intrinsically disordered domain in the central region of IRF-1 (residues 106-140), and this site is sufficient to form a stable complex with CHIP in cells and to compete in trans with full-length IRF-1, leading to a reduction in its ubiquitination. The study reveals a complex relationship between CHIP and IRF-1 and highlights the role that direct binding or "docking" of CHIP to its substrate(s) can play in its mechanism of action as an E3 ligase.

PMID:
20947504
PMCID:
PMC3013021
DOI:
10.1074/jbc.M110.153122
[Indexed for MEDLINE]
Free PMC Article

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