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RING domains act as both substrate and enzyme in a catalytic arrangement to drive self-anchored ubiquitination

DOI: 10.1038/s41467-021-21443-6 DOI Help

Authors: Leo Kiss (Medical Research Council Laboratory of Molecular Biology) , Dean Clift (MRC Laboratory of Molecular Biology) , Nadine Renner (MRC Laboratory of Molecular Biology) , David Neuhaus (MRC Laboratory of Molecular Biology) , Leo C. James (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: February 2021
Diamond Proposal Number(s): 15916 , 21426

Open Access Open Access

Abstract: Attachment of ubiquitin (Ub) to proteins is one of the most abundant and versatile of all posttranslational modifications and affects outcomes in essentially all physiological processes. RING E3 ligases target E2 Ub-conjugating enzymes to the substrate, resulting in its ubiquitination. However, the mechanism by which a ubiquitin chain is formed on the substrate remains elusive. Here we demonstrate how substrate binding can induce a specific RING topology that enables self-ubiquitination. By analyzing a catalytically trapped structure showing the initiation of TRIM21 RING-anchored ubiquitin chain elongation, and in combination with a kinetic study, we illuminate the chemical mechanism of ubiquitin conjugation. Moreover, biochemical and cellular experiments show that the topology found in the structure can be induced by substrate binding. Our results provide insights into ubiquitin chain formation on a structural, biochemical and cellular level with broad implications for targeted protein degradation.

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

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography

Added On: 01/03/2021 11:43


Discipline Tags:

Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)