Identification of RING E3 pseudoligases in the TRIM protein family

Jane Dudley-Fraser, Diego Esposito, Katherine A. McPhie, Coltrane Morley-Williams, Tania Auchynnikava and Katrin Rittinger ()
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Jane Dudley-Fraser: The Francis Crick Institute
Diego Esposito: The Francis Crick Institute
Katherine A. McPhie: The Francis Crick Institute
Coltrane Morley-Williams: The Francis Crick Institute
Tania Auchynnikava: The Francis Crick Institute
Katrin Rittinger: The Francis Crick Institute

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract TRIpartite Motif (TRIM) family proteins have diverse roles across a broad variety of cellular functions, which are largely presumed to depend on their ubiquitin E3 ligase activity, conferred by a RING domain. However, recent reports have shown that some TRIMs lack detectable ubiquitination activity in isolation, despite containing a RING domain. Here, we present parallel in cellulo, in vitro, and in silico structure-function analyses of the ubiquitin E3 ligase activity and RING domain structural characteristics of the whole TRIM protein family. In-depth follow-up studies of this comprehensive dataset reveals a number of ‘pseudoligases’, whose RING domains have structurally diverged at either the homodimerisation or E2~ubiquitin interfaces, thereby disrupting their ability to catalyse ubiquitin transfer. Together, these data raise intriguing open questions regarding the unknown TRIM functions in physiology and disease.

Date: 2025
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DOI: 10.1038/s41467-025-58807-1

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