Publication

Article Metrics

Citations


Online attention

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

DOI: 10.1038/s41467-019-12388-y DOI Help

Authors: Leo Kiss (Medical Research Council Laboratory of Molecular Biology) , Jingwei Zeng (Medical Research Council Laboratory of Molecular Biology) , Claire Dickson (Medical Research Council Laboratory of Molecular Biology; University of New South Wales) , Donna L. Mallery (Medical Research Council Laboratory of Molecular Biology) , Ji-Chun Yang (Medical Research Council Laboratory of Molecular Biology) , Stephen H. Mclaughlin (Medical Research Council Laboratory of Molecular Biology) , Andreas Boland (Medical Research Council Laboratory of Molecular Biology; University of Geneva) , David Neuhaus (Medical Research Council Laboratory of Molecular Biology) , Leo C. James (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 15916

Open Access Open Access

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.

Journal Keywords: Enzyme mechanisms; Ligases; Solution-state NMR; Ubiquitylation; X-ray crystallography

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 17/10/2019 15:42

Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)