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Nat Commun. 2019 Oct 3;10(1):4502. doi: 10.1038/s41467-019-12388-y.

A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases.

Author information

1
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
2
University of New South Wales, Sydney, NSW, Australia.
3
Department of Molecular Biology, Science III, University of Geneva, Geneva, Switzerland.
4
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. lcj@mrc-lmb.cam.ac.uk.

Abstract

The cytosolic antibody receptor TRIM21 possesses unique ubiquitination activity that drives broad-spectrum anti-pathogen targeting and underpins the protein depletion technology Trim-Away. This activity is dependent on formation of self-anchored, K63-linked ubiquitin chains by the heterodimeric E2 enzyme Ube2N/Ube2V2. Here we reveal how TRIM21 facilitates ubiquitin transfer and differentiates this E2 from other closely related enzymes. A tri-ionic motif provides optimally distributed anchor points that allow TRIM21 to wrap an Ube2N~Ub complex around its RING domain, locking the closed conformation and promoting ubiquitin discharge. Mutation of these anchor points inhibits ubiquitination with Ube2N/Ube2V2, viral neutralization and immune signalling. We show that the same mechanism is employed by the anti-HIV restriction factor TRIM5 and identify spatially conserved ionic anchor points in other Ube2N-recruiting RING E3s. The tri-ionic motif is exclusively required for Ube2N but not Ube2D1 activity and provides a generic E2-specific catalysis mechanism for RING E3s.

PMID:
31582740
DOI:
10.1038/s41467-019-12388-y
Free PMC Article

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