InterPro domain: IPR002083

Although apparently functionally unrelated, intracellular TRAFs and extracellular meprins share a conserved region of about 180 residues, the meprin and TRAF homology (MATH) domain [ 1 ]. Meprins are mammalian tissue-specific metalloendopeptidases of the astacin family implicated in developmental, normal and pathological processes by hydrolysing a variety of proteins. Various growth factors, cytokines, and extracellular matrix proteins are substrates for meprins. They are composed of five structural domains: an N-terminal endopeptidase domain, a MAM domain (see PDOC00604 ), a MATH domain, an EGF-like domain (see PDOC00021 ) and a C-terminal transmembrane region. Meprin A and B form membrane bound homotetramer whereas homooligomers of meprin A are secreted. A proteolitic site adjacent to the MATH domain, only present in meprin A, allows the release of the protein from the membrane [ 2 ].

TRAF proteins were first isolated by their ability to interact with TNF receptors [ 3 ]. They promote cell survival by the activation of downstream protein kinases and, finally, transcription factors of the NF-kB and AP-1 family. The TRAF proteins are composed of 3 structural domains: a RING finger (see PDOC00449 ) in the N-terminal part of the protein, one to seven TRAF zinc fingers (see PDOC50145 ) in the middle and the MATH domain in the C-terminal part [ 4 ]. The MATH domain is necessary and sufficient for self-association and receptor interaction. From the structural analysis two consensus sequence recognised by the TRAF domain have been defined: a major one, [PSAT]x[QE]E and a minor one, PxQxxD [ 4 ].

The structure of the TRAF2 protein reveals a trimeric self-association of the MATH domain [ 5 ]. The domain forms a new, light-stranded antiparallel beta sandwich structure. A coiled-coil region adjacent to the MATH domain is also important for the trimerisation. The oligomerisation is essential for establishing appropriate connections to form signalling complexes with TNF receptor-1. The ligand binding surface of TRAF proteins is located in beta-strands 6 and 7 [ 6 ].

1. The new MATH: homology suggests shared binding surfaces in meprin tetramers and TRAF trimers. FEBS Lett. 530, 1-3
2. COOH-terminal proteolytic processing of secreted and membrane forms of the alpha subunit of the metalloprotease meprin A. Requirement of the I domain for processing in the endoplasmic reticulum. J. Biol. Chem. 270, 5449-56
3. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78, 681-92
4. The structural basis for the recognition of diverse receptor sequences by TRAF2. Mol. Cell 4, 321-30
5. Structural basis for self-association and receptor recognition of human TRAF2. Nature 398, 533-8