Journal
EMBO JOURNAL
Volume 24, Issue 24, Pages 4324-4333Publisher
WILEY
DOI: 10.1038/sj.emboj.7600895
Keywords
conjugation; HECT domain; polyubiquitin; ubiquitin; ubiquitin ligase
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Funding
- NIDDK NIH HHS [R01 DK046984, DK46984] Funding Source: Medline
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Individual ubiquitin (Ub)-protein ligases (E3s) cooperate with specific Ub-conjugating enzymes (E2s) to modify cognate substrates with polyubiquitin chains. E3s belonging to the Really Interesting New Gene (RING) and Homologous to E6-Associated Protein (E6AP) C-Terminus (HECT) domain families utilize distinct molecular mechanisms. In particular, HECT E3s, but not RING Us, form a thiol ester with Ub before transferring Ub to the substrate lysine. Here we report that different HECT domain E3s can employ distinct mechanisms of polyubiquitin chain synthesis. We show that E6AP builds up a K48-linked chain on its HECT cysteine residue, while KIAA10 builds up K48- and K29-linked chains as free entities. A small region near the N-terminus of the conserved HECT domain helps to bring about this functional distinction. Thus, a given HECT domain can specify both the linkage of a polyubiquitin chain and the mechanism of its assembly.
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