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, J. Carlos Penedo, Ronald Hay (Lead / Corresponding author)

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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
Early online date30 Jul 2020
DOIs
Publication statusE-pub ahead of print - 30 Jul 2020

Keywords

  • Enzyme mechanisms
  • Molecular conformation
  • Solution-state NMR
  • Ubiquitylation

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