Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity

Diego Esposito, Jane Dudley-Fraser, Acely Garza-Garcia and Katrin Rittinger ()
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Diego Esposito: The Francis Crick Institute
Jane Dudley-Fraser: The Francis Crick Institute
Acely Garza-Garcia: The Francis Crick Institute
Katrin Rittinger: The Francis Crick Institute

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Tripartite motif (TRIM) proteins constitute a large family of RING-type E3 ligases that share a conserved domain architecture. TRIM2 and TRIM3 are paralogous class VII TRIM members that are expressed mainly in the brain and regulate different neuronal functions. Here we present a detailed structure-function analysis of TRIM2 and TRIM3, which despite high sequence identity, exhibit markedly different self-association and activity profiles. We show that the isolated RING domain of human TRIM3 is monomeric and inactive, and that this lack of activity is due to a few placental mammal-specific amino acid changes adjacent to the core RING domain that prevent self-association but not E2 recognition. We demonstrate that the activity of human TRIM3 RING can be restored by substitution with the relevant region of human TRIM2 or by hetero-dimerization with human TRIM2, establishing that subtle amino acid changes can profoundly affect TRIM protein activity. Finally, we show that TRIM2 and TRIM3 interact in a cellular context via their filamin and coiled-coil domains, respectively.

Date: 2022
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DOI: 10.1038/s41467-022-35300-7

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