Understanding the determinants for site-specific ubiquitination by E3 ligase components of the ubiquitin machinery is proving to be a challenge. In the present study we investigate the role of an E3 ligase docking site (Mf2 domain) in an intrinsically disordered domain of IRF-1 [IFN (interferon) regulatory factor-1], a short-lived IFNγ-regulated transcription factor, in ubiquitination of the protein. Ubiquitin modification of full-length IRF-1 by E3 ligases such as CHIP [C-terminus of the Hsc (heat-shock cognate) 70-interacting protein] and MDM2 (murine double minute 2), which dock to the Mf2 domain, was specific for lysine residues found predominantly in loop structures that extend from the DNA-binding domain, whereas no modification was detected in the more conformationally flexible C-terminal half of the protein. The E3 docking site was not available when IRF-1 was in its DNA-bound conformation and cognate DNA-binding sequences strongly suppressed ubiquitination, highlighting a strict relationship between ligase binding and site-specific modification at residues in the DNA-binding domain. Hyperubiquitination of a non-DNA-binding mutant supports a mechanism where an active DNA-bound pool of IRF-1 is protected from polyubiquitination and degradation.
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Research Article|
January 09 2013
DNA-binding regulates site-specific ubiquitination of IRF-1
Vivien Landré;
Vivien Landré
*Cell Signalling Unit, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XR, U.K.
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Emmanuelle Pion;
Emmanuelle Pion
1
*Cell Signalling Unit, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XR, U.K.
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Vikram Narayan;
Vikram Narayan
*Cell Signalling Unit, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XR, U.K.
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Dimitris P. Xirodimas;
Dimitris P. Xirodimas
†Centre de Recherche de Biochimie Macromoléculaire, UMR 5237, CNRS, Montpellier, France
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Kathryn L. Ball
Kathryn L. Ball
2
*Cell Signalling Unit, Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XR, U.K.
2To whom correspondence should be addressed (email Kathryn.Ball@igmm.ed.ac.uk).
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Publisher: Portland Press Ltd
Received:
July 05 2012
Revision Received:
October 31 2012
Accepted:
November 08 2012
Accepted Manuscript online:
November 08 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 449 (3): 707–717.
Article history
Received:
July 05 2012
Revision Received:
October 31 2012
Accepted:
November 08 2012
Accepted Manuscript online:
November 08 2012
Citation
Vivien Landré, Emmanuelle Pion, Vikram Narayan, Dimitris P. Xirodimas, Kathryn L. Ball; DNA-binding regulates site-specific ubiquitination of IRF-1. Biochem J 1 February 2013; 449 (3): 707–717. doi: https://doi.org/10.1042/BJ20121076
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