Article
- The EMBO Journal (2006) 25, 1710 - 1719
- doi:10.1038/sj.emboj.7601061
Published online: 6 April 2006
Subject Category:
Molecular determinants of polyubiquitin linkage selection by an HECT ubiquitin ligase
Min Wang1, Dongmei Cheng2, Junmin Peng2 and Cecile M Pickart1
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
- Department of Human Genetics, Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA
Correspondence to:
Cecile M Pickart, Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street/Room W8030, Baltimore, MD 21205, USA. Tel.: +1 410 614 4554; Fax: +1 410 955 2926; E-mail: cpickart@jhmi.edu
Received 22 November 2005; Accepted 3 March 2006
Abstract
Ubiquitin (Ub)-protein ligases (E3s) frequently modify their substrates with multiple Ub molecules in the form of a polyubiquitin (poly-Ub) chain. Although structurally distinct poly-Ub chains (linked through different Ub lysine (Lys) residues) can confer different fates on target proteins, little is known about how E3s select the Lys residue to be used in chain synthesis. Here, we used a combination of mutagenesis, biochemistry, and mass spectrometry to map determinants of linkage choice in chain assembly catalyzed by KIAA10, an HECT (Homologous to E6AP C-Terminus) domain E3 that synthesizes K29- and K48-linked chains. Focusing on the Ub molecule that contributes the Lys residue for chain formation, we found that specific surface residues adjacent to K48 and K29 are critical for the usage of the respective Lys residues in chain synthesis. This direct mechanism of linkage choice bears similarities to the mechanism of substrate site selection in sumoylation catalyzed by Ubc9, but is distinct from the mechanism of chain linkage selection used by the Mms2/Ubc13 (Ub E2 variant (UEV)/E2) complex.
Keywords:
- chain linkage,
- HECT domain,
- polyubiquitin chains,
- ubiquitin,
- ubiquitin ligase
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