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

Nat Commun. 2022 Dec 8;13(1):7583. doi: 10.1038/s41467-022-35300-7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids*
  • Carrier Proteins* / genetics
  • Humans
  • Tripartite Motif Proteins* / genetics
  • Ubiquitin-Protein Ligases* / genetics

Substances

  • Amino Acids
  • Carrier Proteins
  • TRIM3 protein, human
  • Ubiquitin-Protein Ligases
  • TRIM2 protein, human
  • Tripartite Motif Proteins