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

Leo Kiss, Jingwei Zeng, Claire F. Dickson, Donna L. Mallery, Ji-Chun Yang, Stephen H. McLaughlin, Andreas Boland, David Neuhaus and Leo C. James ()
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Leo Kiss: Medical Research Council Laboratory of Molecular Biology
Jingwei Zeng: Medical Research Council Laboratory of Molecular Biology
Claire F. Dickson: Medical Research Council Laboratory of Molecular Biology
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
David Neuhaus: Medical Research Council Laboratory of Molecular Biology
Leo C. James: Medical Research Council Laboratory of Molecular Biology

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12388-y

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