Work

RING E3 ligase TRIM8 is structurally selective for UBE2N-mediated ubiquitination

Year: 2026

Type: article

Abstract: RING domains catalyze ubiquitination by stabilizing a closed conformation of E2-ubiquitin (Ub) conjugates, with TRIpartite Motif (TRIM) proteins representing the largest subfamily of RING-type E3 ligases. TRIM proteins are implicated in many physiological processes and diseases. For example, TRIM8 perturbation has been variously linked to neurodevelopmental defects and several cancer types, attributed to its ubiquitination of a myriad of putative substrates. However, the molecular mechanisms behind these modifications are not yet clear. Here we show that TRIM8 has preferential functionality with the E2 enzyme UBE2N to generate K63-linked poly-ubiquitin chains. By solving the crystal structure of TRIM8 RING bound to a UBE2N-Ub conjugate, we discover that its non-canonical asparagine "linchpin" residue belies this selectivity by failing to form key contacts required to stabilize the closed conformation of other E2 enzymes. These findings not only open the door to exploring the impact of TRIM8-mediated K63 chain formation in health and disease but also add to a growing appreciation of the specificities of RING domain catalytic activity.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113642

Authors: Jane Dudley-Fraser, Diego Esposito, Katrin Rittinger

Institution: The Francis Crick Institute

Language: English

Topic: Ubiquitin and proteasome pathways

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $3,430

Funders: Wellcome Trust, Francis Crick Institute, Cancer Research UK, Medical Research Council