The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
TRAF2 group (TRAF1,2,3,5) MATH domain binding motifs
Functional site description:
Ring finger E3 ligase TRAF2 specifically interacts with TNF receptor superfamily members and connects the receptors to downstream signalling proteins. The receptor binding groove of the TRAF2 MATH domain is similar to that of TRAF1, 3 and 5, but dissimilar to those of TRAF4 and 6. TRAF2 forms complexes with other RING E3 ligases cIAP1/2 for Lys63-linked polyubiquitination and NF-κB activation. The Lys63-Ub chains are not signals for destruction so this motif is not a degron. This process is central to the NF-κB gene activation pathways based on surface receptor signalling. Bound TNFRs, including CD30, CD40, CD27 and Ox40, elicit cellular processes involved in developmental, immunological and inflammatory signalling. There are at least two types of PxQ-based TRAF2-like-binding motifs (short or “major” and long or “minor”). TRAF3 has a specific PxP-based variant in addition to binding the shared motifs. The TRAF2-binding motif is mimicked in the proteins of some pathogens, such as Epstein-Barr virus.
ELMs with same func. site: LIG_TRAF2like_MATH_loPxQ_2  LIG_TRAF2like_MATH_shPxQ_1  LIG_TRAF3_MATH_PxP_3 
ELM Description:
The TRAF2 MATH domain can accommodate short (major) or long (minor) variants of its TBM. TRAF2 uses three binding hotspots for motif recognition. These regions are also highly conserved in TRAF1, 3 and 5 (except one of the serine residues in the serine triad is replaced by an alanine in TRAF1) and hence they have overlapping substrate specificities. The short motif is 4 residues in length and has three key positions mainly matching the consensus sequence PxQ(ED). The first position is always proline in the short motif. The proline at the first position makes extensive van der Waals contacts with the hot spot 1 forming residues (F410, L432, F447, F456, and C469) in TRAF2. The +2 position makes backbone β-augmentation to the MATH β-strand 7 and its sidechain is always bulky, probably shielding the backbone H-bonding. Pro is not allowed at this position. The key anchoring residue at the +3 position is Gln that interacts with serine triad residues (S453, S454, and S455) in hot spot 2. Gln at this position forms hydrogen bonds with all three serine residues and forms the strongest anchoring point in the interaction. An acidic residue occupies the +4 position: Glu engages in an ion-pair interaction with the side chain guanidinium group of R393 and also forms an H-bond with Y395 in TRAF2 (1QSC). Amino acid replacements for the PxQ(ED) short motif were specifically tested by peptide SPOT array (Pullen,1999) broadly confirming the preferences for this motif for TRAF1, TRAF2 and TRAF3. The SPOT arrays suggest Ser and Thr at the +5 position but this is not confirmed in sequence alignments.
The shorter Asp residue at the +4 position H-bonds with Y458 of TRAF3 and to a fixed water molecule (4GHU). In some structures with longer TBM peptides there is extended binding after the motif by several residues (e.g. 1FLL) but here the sequence seems less conserved and has not been included in the motif pattern.
Pattern Probability: 0.0004319
Present in taxon: Eukaryota
Interaction Domains:
  • MATH (PF00917) MATH domain (Stochiometry: 1 : 1)
  • TRAF3, MATH domain (IPR037304) Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is a highly versatile regulator that positively controls type I interferon production, but negatively regulates mitogen-activated protein (MAP) kinase activation and non-canonical nuclear factor-kB signalling (Stochiometry: 1 : 1)
  • TNF receptor-associated factor 2, MATH domain (IPR037305) TNF receptor-associated factor 2 (TRAF2) regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis (Stochiometry: 1 : 1)
  • TNF receptor-associated factor 1, MATH domain (IPR037306) TNF receptor-associated factor 1 (TRAF1) plays a role in the regulation of cell survival and apoptosis (Stochiometry: 1 : 1)
PDB Structure: 1RF3
o See 13 Instances for LIG_TRAF2like_MATH_shPxQ_1
o Abstract
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).
o 14 selected references:

o 15 GO-Terms:

o 13 Instances for LIG_TRAF2like_MATH_shPxQ_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q8VCF0 Mavs
143 146 RETPSCPKPVQDTQPPESPV TP 4 Mus musculus (House mouse)
Q07011 TNFRSF9
231 234 IFKQPFMRPVQTTQEEDGCS TP 2 Homo sapiens (Human)
P47741 Tnfrsf4
257 260 CWGNSFRTPIQEEHTDAHFT TP 3 Mus musculus (House mouse)
607 610 GLREPEKASRPVQEQGGAKA TP 3 Homo sapiens (Human)
143 146 EKEPSYPMPVQETQAPESPG TP 3 Homo sapiens (Human)
Q16512 PKN1
580 583 SSPSSLSSPIQESTAPELPS TP 5 Homo sapiens (Human)
Q13627 DYRK1A
583 586 TQVTVETHPVQETTFHVAPQ TP 3 Homo sapiens (Human)
P18347 1
60 63 NPYCLLGHPVQESGCPGRPT TP 3 Herpesvirus saimiri (strain 11)
P25942 CD40
250 253 LPGSNTAAPVQETLHGCQPV TP 2 Homo sapiens (Human)
P43489 TNFRSF4
262 265 PGGGSFRTPIQEEQADAHST TP 2 Homo sapiens (Human)
P36941 LTBR
402 405 PGPPGLSTPHQEDGKAWHLA TP 2 Homo sapiens (Human)
P28908 TNFRSF8
561 564 EADHTPHYPEQETEPPLGSC TP 1 Homo sapiens (Human)
P26842 CD27
246 249 REEEGSTIPIQEDYRKPEPA TP 1 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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