Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer

Paul Murphy, Yingqi Xu, Sarah L. Rouse, Ellis G Jaffray, Anna Plechanovova, Steve J. Matthews, Carlos Penedo, Ronald T. Hay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
2 Downloads (Pure)

Abstract

The human genome contains an estimated 600 ubiquitin E3 ligases, many of which are single-subunit E3s (ssE3s) that can bind to both substrate and ubiquitin-loaded E2 (E2~Ub). Within ssE3s structural disorder tends to be located in substrate binding and domain linking regions. RNF4 is a ssE3 ligase with a C-terminal RING domain and disordered N-terminal region containing SUMO Interactions Motifs (SIMs) required to bind SUMO modified substrates. Here we show that, although the N-terminal region of RNF4 bears no secondary structure, it maintains a compact global architecture primed for SUMO interaction. Segregated charged regions within the RNF4 N-terminus promote compaction, juxtaposing RING domain and SIMs to facilitate substrate ubiquitination. Mutations that induce a more extended shape reduce ubiquitination activity. Our result offer insight into a key step in substrate ubiquitination by a member of the largest ubiquitin ligase subtype and reveal how a defined architecture within a disordered region contributes to E3 ligase function.
Original languageEnglish
Article number3807
Number of pages13
JournalNature Communications
Volume11
DOIs
Publication statusPublished - 30 Jul 2020

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