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

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Listed:
  • 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
    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
    Science III, University of Geneva)

  • David Neuhaus

    (Medical Research Council Laboratory of Molecular Biology)

  • Leo C. James

    (Medical Research Council Laboratory of Molecular Biology)

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.

Suggested Citation

  • Leo Kiss & Jingwei Zeng & Claire F. Dickson & Donna L. Mallery & Ji-Chun Yang & Stephen H. McLaughlin & Andreas Boland & David Neuhaus & Leo C. James, 2019. "A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12388-y
    DOI: 10.1038/s41467-019-12388-y
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    Cited by:

    1. Frank Herkules & Corey H. Yu & Alexander B. Taylor & Vi Dougherty & Susan T. Weintraub & Dmitri N. Ivanov, 2022. "Structural and functional asymmetry of RING trimerization controls priming and extension events in TRIM5α autoubiquitylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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