RESUMEN
The tripartite motif (TRIM) protein family members have been implicated in a multitude of physiologies and pathologies in different tissues. With diverse functions in cellular processes including regulation of signaling pathways, protein degradation, and transcriptional control, the impact of TRIM dysregulation can be multifaceted and complex. Here, we focus on the cellular and molecular roles of TRIMs identified in the brain in the context of a selection of pathologies including cancer and neurodegeneration. By examining each disease in parallel with described roles in brain development, we aim to highlight fundamental common mechanisms employed by TRIM proteins and identify opportunities for therapeutic intervention.
RESUMEN
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.