Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis

Anna Plechanovova, Ellis G. Jaffray, Michael Howard Tatham, Jim Naismith, Ronald Thomas Hay

Research output: Contribution to journalArticlepeer-review

403 Citations (Scopus)

Abstract

Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING domain of rat RNF4 in complex with E2 (UbcH5A) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The carboxy-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilize the consequent tetrahedral transition-state intermediate.

Original languageEnglish
Pages (from-to)115-120
JournalNature
Volume489
Issue number7414
Early online date29 Jul 2012
DOIs
Publication statusPublished - 6 Sept 2012

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