The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
Motif which binds to the MATH domain of the TRAF6 K63 E3 ligase
Functional site description:
This motif interaction facilitates an important signalling centre in innate immunity. The Ring Finger-type E3 ligase TRAF6 cooperates with the heterodimeric UBE2N and UBE2V1 E2 ligase which catalyses Lys63-linked polyubiquitin chains on proteins docked to the C-terminal MATH (TRAF-C) domain of TRAF6. Lys63-Ub chains are not signals for destruction, so this motif is not a degron. The process is central to the NF-κB gene activation pathways based on surface receptor signalling, such as via the RANK, TLR and CD40 receptors. This information-transmitting cellular process is used in developmental, immunological and inflammatory signalling. Some substrates have more than one TRAF6-binding motif, facilitating the cooperative assembly of large regulatory complexes. The TRAF6-binding motif is mimicked in the proteins of some pathogens, such as herpesviruses.

ELM Description:
Polypeptides which contain this motif bind to the TRAF6 MATH domain by β-augmentation, imparting rigidity to the binding conformation. The motif has three key positions matching PxExx[DE(Ar)] (where (Ar) is an aromatic residue). Position +1 is always Pro, fitting in a surface groove sandwiched between Phe471 and Tyr473 of human TRAF6. Position +3 is always Glu which fully extends to make a charged H-bond to the backbone peptide NH of Ala458. Position +6 is either a negatively charged residue or an aromatic residue. In the structure of TifA peptide bound to TRAF6 (6A33), the +6 Glu makes a double salt-bridge to Arg466 of TRAF6 (Huang,2019). In the structure of CD40 peptide bound to TRAF6 (1LB5), the +6 Tyr stacks onto the guanidinium group of Arg392 (Ye,2002). Positions +2 and +4 cannot be Pro because their peptide NH groups H-bond to the edge β strand. A few residues on either side of the core motif are not conserved but can be seen in the bound structures and are included as flexible positions in the ELM pattern.
Pattern: ..P[^P]E[^P].[FYWHDE].
Pattern Probability: 0.0014066
Present in taxon: Vertebrata
Interaction Domains:
o See 34 Instances for LIG_TRAF6_MATH_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). The family is named for its association with members of the TNFR membrane receptor superfamily (Rothe,1994) but TRAFs also interact with a number of soluble cytosolic proteins. Most 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).

For some but not all TRAFs, the SLiMs are known. The core motif, in the case of TRAF6, is PxExx[DE(Ar)] (where (Ar) is an aromatic residue) (Darnay,1999). TRAF6 interacts with the UBE2N and UBE2V1 heterodimeric E2 ligase which catalyses Lys63-linked polyubiquitin chains (Deng,2000) on substrate proteins docked to the C-terminal MATH (TRAF-C) domain of TRAF6. TRAF6 homotrimerises and some substrates have more than one binding motif in their regions of intrinsically unstructured peptide.

TRAF6 is directly involved in bone development and maintenance (Yamamoto,2021). The activation of NF-κB and NFATc1 is required for the development of the bone resorbing osteoclasts, large multinucleate cells derived from fused monocytes. In precursor cells, binding of the cytokine RANKL (Tnfsf11) to RANK (TNF family receptor Tnfrsf11a) activates the signalling pathway. Trimeric RANK binds TRAF6 trimer using three TRAF6 interacting motifs, enabling cooperative complex formation. This leads to NF-κB expression which together with increased Ca2+ signalling then activates NFATc1 expression, which enables osteoclast maturation. TRAF6 knockout mice have bone resorption defects (Lomaga,1999).

TRAF6 is essential for innate immunity signalling in macrophages initiated by Toll-Like Receptors, TLRs (Yamamoto,2021). In the presence of bacterial components such as lipopolysaccharide, surface receptors TLR2, 4, and 6 stimulate the formation of a large oligomeric complex, the MyDDosome, assembled from activated MyD88 and IRAK kinases (Cohen,2020). Endosomal receptors TLR-7 and 9 responding to the presence of nucleic acid (often of viral origin) in these vesicles also stimulate the MyDDosome complex (Yamamoto,2021). Recruitment of TRAF6 by binding motifs in the C-terminal tails of IRAK1, 2, 3 leads to NF-κB activation via the IKK kinase complex.

CD40 (TNFRSF5) is another receptor which signals through TRAF6 (and other TRAFs) in multiple immune cells and other contexts, for example, acting as a coregulator of B cell activation by helper T cells (Yamamoto,2021).

Double-stranded RNA in the cytosol is indicative of viral infection and is detected by RIG-I-like receptors (RLRs) which then induce the mitochondrial surface protein MAVS to self-polymerise (Chathuranga,2021). The resultant MAVS signalosome recruits TRAF6 which participates in NF-κB activation and also IRF-7 activation, the latter inducing type-1 interferon gene expression. DNA in the cytosol is also indicative of pathogen infection: In Teleost fish (but not in mammals), a TRAF6-binding motif in the cytosolic tail of STING, located on the ER, enables similar downstream signalling (de Oliveira Mann,2019).

Of pathogens known to hijack the TRAF6 signalling pathway using motif mimicry, herpesviruses are the most studied. The bovine herpesvirus E3 ligase BICP0 converts the binding motif into a degron and induces K48 polyubiquitination, targeting TRAF6 for destruction by the proteasome (Cao,2019). The T cell-tropic Herpesvirus ateles recruits TRAF6 to stimulate NF-κB signalling (Heinemann,2006). Similarly, HSV U(L)37 also binds TRAF6 for NF-κB stimulation as required for viral replication (Liu,2008).
o 10 selected references:

o 22 GO-Terms:

o 34 Instances for LIG_TRAF6_MATH_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P51617 IRAK1
IRAK1_HUMAN
583 591 LQRGPNQPVESDESLGGLSA TP 2 Homo sapiens (Human)
1 
Q66677 E10
VCLAP_EHV2
276 284 LGGLPPDPQEVDDPSLSVQG TP 2 Equid herpesvirus type 2 strain 86/87
1 
Q15654 TRIP6
TRIP6_HUMAN
48 56 RVNFCPLPSEQCYQAPGGPE TP 3 Homo sapiens (Human)
1 
Q9HAV5-2 EDA2R
TNR27_HUMAN
270 278 HSHWVHSPIECTELDLQKFS U 3 Homo sapiens (Human)
1 
Q7Z434 MAVS
MAVS_HUMAN
453 461 GMGPCHGPEENEYKSEGTFG TP 6 Homo sapiens (Human)
1 
Q7Z434 MAVS
MAVS_HUMAN
151 159 ETQAPESPGENSEQALQTLS TP 2 Homo sapiens (Human)
1 
Q9UDY8 MALT1
MALT1_HUMAN
802 810 HFSRSNVPVETTDEIPFSFS TP 2 Homo sapiens (Human)
1 
Q96S59 RANBP9
RANB9_HUMAN
319 327 PTVGLQTPGEVVDANFGQHP TP 5 Homo sapiens (Human)
1 
Q9YJQ8 Protein tio
TIO_ATHV3
3 11 MANEPQEHEEGKPFFPPLGD TP 3 Ateline herpesvirus 3
1 
P29128 BICP0
ICP0_BHV1J
344 352 GAARARRPAERQYVSTRGRQ TP 3 Bovine herpesvirus type 1.1 (strain Jura)
1 
Q8IUC6 TICAM1
TCAM1_HUMAN
248 256 VPGGCQEPEEMSWPPSGEIA TP 2 Homo sapiens (Human)
Q8N7N6 Traf3ip2
CIKS_MOUSE
26 34 KPIPEYSPEEELEPPAPNTR TP 5 Mus musculus (House mouse)
Q8IU57-1 IFNLR1
INLR1_HUMAN
478 486 TFCWESSPEEEEEARESEIE TP 4 Homo sapiens (Human)
1 
E7F4N7 sting1
STING_DANRE
380 388 PQSLRSEPVETTDYFNPSSA TP 1 Danio rerio (Zebrafish)
1 
Q96CG3 TIFA
TIFA_HUMAN
174 182 TYSLCSSQSSSPTEMDENES TP 4 Homo sapiens (Human)
1 
P51617 IRAK1
IRAK1_HUMAN
702 710 PGLGLEQDRQGPEESDEFQS TP 2 Homo sapiens (Human)
1 
P51617 IRAK1
IRAK1_HUMAN
540 548 ASCIPPSPQENSYVSSTGRA TP 2 Homo sapiens (Human)
1 
O35305 Tnfrsf11a
TNR11_MOUSE
338 346 GDLSRKIPTEDEYTDRPSQP TP 3 Mus musculus (House mouse)
1 
Q9Y6Q6 TNFRSF11A
TNR11_HUMAN
342 350 EDSFRQMPTEDEYMDRPSQP TP 3 Homo sapiens (Human)
1 
P25942 CD40
TNR5_HUMAN
231 239 APHPKQEPQEINFPDDLPGS TP 4 Homo sapiens (Human)
1 
P97300-2 Nptn
NPTN_MOUSE
363 371 VYEKRKRPDEVPDDDEPAGP TP 5 Mus musculus (House mouse)
1 
P10221 UL37
V120_HHV11
1097 1105 GAPHSNTPVEDDEMIPEDTV TP 3 Herpes simplex virus (type 1 / strain 17)
1 
O43187 IRAK2
IRAK2_HUMAN
524 532 TGSSSNTPEETDDVDNSSLD TP 1 Homo sapiens (Human)
O35305 Tnfrsf11a
TNR11_MOUSE
371 379 SIPPFQEPLEVGENDSLSQC TP 1 Mus musculus (House mouse)
O35305 Tnfrsf11a
TNR11_MOUSE
445 453 YTGSGNTPGEDHEPFPGSLK TP 1 Mus musculus (House mouse)
P27512 Cd40
TNR5_MOUSE
235 243 PAARRQDPQEMEDYPGHNTA TP 2 Mus musculus (House mouse)
O43187 IRAK2
IRAK2_HUMAN
555 563 GAATPLLPTENGEGRLRVIV TP 1 Homo sapiens (Human)
Q9Y6Q6 TNFRSF11A
TNR11_HUMAN
375 383 STPPFSEPLEVGENDSLSQC TP 1 Homo sapiens (Human)
Q9Y6Q6 TNFRSF11A
TNR11_HUMAN
451 459 CTGCRNPPGEDCEPLVGSPK TP 1 Homo sapiens (Human)
Q62406 Irak1
IRAK1_MOUSE
537 545 AGHGSPSPQENSYMSTTGSA TP 1 Mus musculus (House mouse)
Q62406 Irak1
IRAK1_MOUSE
580 588 LQRSPNQPVESDESVPGLSA TP 1 Mus musculus (House mouse)
Q62406 Irak1
IRAK1_MOUSE
700 708 GLDLEPEKSQGPEESDEFQS TP 1 Mus musculus (House mouse)
O35305 Tnfrsf11a
TNR11_MOUSE
72 80 SVCLPCGPDEYLDTWNEEDK FP 1 Mus musculus (House mouse)
Q9Y6Q6 TNFRSF11A
TNR11_HUMAN
71 79 SVCLPCGPDEYLDSWNEEDK FP 1 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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