LIG_TRAF3_MATH_PxP_3

The Tumour necrosis factor Receptor-Associated Factors (TRAFs) are a family of seven Ring-type E3 ligases, most of which have a C-terminal MATH domain that interacts with substrates containing the appropriate SLiM (Yamamoto,2021), which has been termed TBM (TRAF-Binding Motif). The TRAF family is named for its association with members of the TNFR membrane receptor superfamily (Rothe,1994), but TRAFs also interact with numerous cytosolic proteins such as the TANK adaptor protein (Q92844). TRAF proteins play critical roles in the transmission of signals from the surface receptors leading to the activation of NF-κB gene expression. TRAF6, along with 2 and 5, acts in the canonical activation pathway, while TRAF2 and 3 act in the non-canonical pathway (Yamamoto,2021). A striking feature of TRAF6 cell biology is that the sets of interacting proteins may be completely different in the various signalling systems in which it participates (Yamamoto,2021; Chathuranga,2021; Dainichi,2019). TRAF1,2,3 and 5 MATH domains share the highest sequence identity to one another and may have evolved through gene duplication subsequent to earlier divergence from the TRAF4 and 6 homologues (Foight,2016). The sequence identity trend holds similarly among TRAF1,2,3 and 5 when the core peptide binding site is considered (Foight,2016). Different binding motifs have been defined for TRAFs1,2,3 and 5 versus TRAF4 and 6. The residues in the three binding hotspots of TRAF1,2,3 and 5 are highly conserved, indicating they share many common substrates with a similar mode of interaction (Park,2018). There are two variant motifs for TRAF2 binding, mainly based on the length. The short motif with consensus PxQE has been termed the major motif, and the longer motif with consensus PxQxxD as the minor motif. Many of the TNF-R family members like CD30, CD40, OX40, CD27 and 4-1BB (CD137) contain the shorter motif. DYRK1A is a newly identified binding partner of TRAF2 that contains the short motif (Zhang,2021).
TANK (also known as I-TRAF) possesses a C-terminally extended motif (1L0A; 1KZZ). It acts as an inhibitor of TRAF function by competitively binding versus the TRAF2 binding motifs in CD40, TNFR2 and EBV LMP1. The LMP1 protein of Epstein-Barr virus also contains a longer motif that is involved in NF-kB activation (Kaye,1996). Various studies have shown that many of the TRAF2 binding sites are also recognised by other TRAFs like TRAF1,3 and 5 with different affinity and that is important for their different functions in TRAF-mediated signal transduction (Foight,2016). SPOT arrays confirm the overall similarity of the short motif preferences for this group (Pullen,1999).
In addition to recognising PxQ motifs, unlike TRAFs1, 2 and 5, TRAF3 can also uniquely recognise a PxP variant motif found in BAFF-R and TNFR3 (Ni,2004; Li,2003).