Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer
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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.
Murphy , P , Xu , Y , Rouse , S L , Jaffray , E G , Plechanovova , A , Matthews , S J , Penedo , C & Hay , R T 2020 , ' Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer ' , Nature Communications , vol. 11 , 3807 . https://doi.org/10.1038/s41467-020-17647-x
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DescriptionFunding: Wellcome Trust Investigator Awards (098391/Z/12/Z and 217196/Z/19/Z) and Cancer Research UK Programme grant (C434/A21747) to R.T.H., Wellcome Trust Studentship (109113/Z/15/Z) to P.M., Wellcome Trust Collaborative Award (215539) and multiuser equipment grant (104833) to S.J.M. Additionally J.C.P. thanks the Scottish Universities Physics Alliance (SUPA) and the University of St. Andrews for financial support.
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