MATH (meprin and TRAF-C homology) domain; an independent folding unit with an eight-stranded beta-sandwich structure found in meprins, TRAFs and other proteins. Meprins comprise a class of extracellular metalloproteases which are anchored to the membrane and are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. TRAF molecules serve as adapter proteins that link cell surface receptors of the Tumor Necrosis Factor and 1nterleukin-1/Toll-like families to downstream kinase cascades, which results in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses in the immune and inflammatory systems. Other members include the ubiquitin ligases, TRIM37 and SPOP, and the ubiquitin-specific proteases, HAUSP and Ubp21p. A large number of uncharacterized members mostly from lineage-specific expansions in C. elegans and rice contain MATH and BTB domains, similar to SPOP. The MATH domain has been shown to bind peptide/protein substrates in TRAFs and HAUSP. It is possible that the MATH domain in other members of this superfamily also interacts with various protein substrates. The TRAF domain may also be involved in the trimerization of TRAFs. Based on homology, it is postulated that the MATH domain in meprins may be involved in its tetramer assembly and that the MATH domain, in general, may take part in diverse modular arrangements defined by adjacent multimerization domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15230973   7 NKFRWVIKNFSSLGSERVFSDIFVVGSCKWRLMAYPKGVRDN-RCFSLFLVVTDFKTLPCDWKRHTRLRLNVVNQLSEEL 85
Cdd:cd00121   1 GKHTWKIVNFSELEGESIYSPPFEVGGYKWRIRIYPNGDGESgDYLSLYLELDKGESDLEKWSVRAEFTLKLVNQNGGKS 80

                        90       100       110
                ....*....|....*....|....*....|...
gi 15230973  86 SILKETQMWFDQKTPAWGFLAMLPLTELKAENG 118
Cdd:cd00121  81 LSKSFTHVFFSEKGSGWGFPKFISWDDLEDSYY 113

MATH (meprin and TRAF-C homology) domain; an independent folding unit with an eight-stranded beta-sandwich structure found in meprins, TRAFs and other proteins. Meprins comprise a class of extracellular metalloproteases which are anchored to the membrane and are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. TRAF molecules serve as adapter proteins that link cell surface receptors of the Tumor Necrosis Factor and 1nterleukin-1/Toll-like families to downstream kinase cascades, which results in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses in the immune and inflammatory systems. Other members include the ubiquitin ligases, TRIM37 and SPOP, and the ubiquitin-specific proteases, HAUSP and Ubp21p. A large number of uncharacterized members mostly from lineage-specific expansions in C. elegans and rice contain MATH and BTB domains, similar to SPOP. The MATH domain has been shown to bind peptide/protein substrates in TRAFs and HAUSP. It is possible that the MATH domain in other members of this superfamily also interacts with various protein substrates. The TRAF domain may also be involved in the trimerization of TRAFs. Based on homology, it is postulated that the MATH domain in meprins may be involved in its tetramer assembly and that the MATH domain, in general, may take part in diverse modular arrangements defined by adjacent multimerization domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15230973   7 NKFRWVIKNFSSLGSERVFSDIFVVGSCKWRLMAYPKGVRDN-RCFSLFLVVTDFKTLPCDWKRHTRLRLNVVNQLSEEL 85
Cdd:cd00121   1 GKHTWKIVNFSELEGESIYSPPFEVGGYKWRIRIYPNGDGESgDYLSLYLELDKGESDLEKWSVRAEFTLKLVNQNGGKS 80

                        90       100       110
                ....*....|....*....|....*....|...
gi 15230973  86 SILKETQMWFDQKTPAWGFLAMLPLTELKAENG 118
Cdd:cd00121  81 LSKSFTHVFFSEKGSGWGFPKFISWDDLEDSYY 113

MATH domain; This motif has been called the Meprin And TRAF-Homology (MATH) domain. This domain is hugely expanded in the nematode C. elegans.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15230973    13 IKNFSSL-GSERVFSDIFVVGSCKWRLMAYPKGvrDNrcFSLFLVVTDFKTLPCDWKRHTRLRLNVVNQLSEelSILKET 91
Cdd:pfam00917   1 IKNFSKIkEGESYYSPVEERFNIPWRLQIYRKG--GF--LGLYLHCDKEEELERGWSIETEFTLKLVSSNGK--SVTKTD 74

                          90       100
                  ....*....|....*....|....*.
gi 15230973    92 QMWFDQKTpAWGFLAMLPLTELKAEN 117
Cdd:pfam00917  75 THVFEKPK-GWGWGKFISWDDLEKDY 99

MATH (meprin and TRAF-C homology) domain; an independent folding unit with an eight-stranded beta-sandwich structure found in meprins, TRAFs and other proteins. Meprins comprise a class of extracellular metalloproteases which are anchored to the membrane and are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. TRAF molecules serve as adapter proteins that link cell surface receptors of the Tumor Necrosis Factor and 1nterleukin-1/Toll-like families to downstream kinase cascades, which results in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses in the immune and inflammatory systems. Other members include the ubiquitin ligases, TRIM37 and SPOP, and the ubiquitin-specific proteases, HAUSP and Ubp21p. A large number of uncharacterized members mostly from lineage-specific expansions in C. elegans and rice contain MATH and BTB domains, similar to SPOP. The MATH domain has been shown to bind peptide/protein substrates in TRAFs and HAUSP. It is possible that the MATH domain in other members of this superfamily also interacts with various protein substrates. The TRAF domain may also be involved in the trimerization of TRAFs. Based on homology, it is postulated that the MATH domain in meprins may be involved in its tetramer assembly and that the MATH domain, in general, may take part in diverse modular arrangements defined by adjacent multimerization domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15230973   7 NKFRWVIKNFSSLGSERVFSDIFVVGSCKWRLMAYPKGVRDN-RCFSLFLVVTDFKTLPCDWKRHTRLRLNVVNQLSEEL 85
Cdd:cd00121   1 GKHTWKIVNFSELEGESIYSPPFEVGGYKWRIRIYPNGDGESgDYLSLYLELDKGESDLEKWSVRAEFTLKLVNQNGGKS 80

                        90       100       110
                ....*....|....*....|....*....|...
gi 15230973  86 SILKETQMWFDQKTPAWGFLAMLPLTELKAENG 118
Cdd:cd00121  81 LSKSFTHVFFSEKGSGWGFPKFISWDDLEDSYY 113

Ubiquitin-specific protease 21 (Ubp21p) family, MATH domain; composed of fungal proteins with similarity to Ubp21p of fission yeast. Ubp21p is a deubiquitinating enzyme that may be involved in the regulation of the protein kinase Prp4p, which controls the formation of active spliceosomes. Members of this family are similar to human HAUSP (Herpesvirus-associated ubiquitin-specific protease) in that they contain an N-terminal MATH domain and a C-terminal catalytic protease (C19 family) domain. HAUSP is also an ubiquitin-specific protease that specifically catalyzes the deubiquitylation of p53 and MDM2. The MATH domain of HAUSP contains the binding site for p53 and MDM2. Similarly, the MATH domain of members in this family may be involved in substrate binding.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 15230973   9 FRWVIKNFSSLGsERVFSDIFVVGSCKWRLMAYPKGVRDNRCFSLFL----VVTDFKTLPCDW 67
Cdd:cd03775   3 FTWRIKNWSELE-KKVHSPKFKCGGFEWRILLFPQGNSQTGGVSIYLephpEEEEKAPLDEDW 64

Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) family, N-terminal MATH (TRAF-like) domain; composed of proteins similar to human HAUSP, an enzyme that specifically catalyzes the deubiquitylation of p53 and MDM2, hence playing an important role in the p53-MDM2 pathway. It contains an N-terminal TRAF-like domain and a C-terminal catalytic protease (C19 family) domain. The tumor suppressor p53 protein is a transcription factor that responds to many cellular stress signals and is regulated primarily through ubiquitylation and subsequent degradation. MDM2 is a RING-finger E3 ubiquitin ligase that promotes p53 ubiquitinylation. p53 and MDM2 bind to the same site in the N-terminal TRAF-like domain of HAUSP in a mutually exclusive manner. HAUSP also interacts with the Epstein-Barr nuclear antigen 1 (EBNA1) protein of the Epstein-Barr virus (EBV), which efficiently immortalizes infected cells predisposing the host to a variety of cancers. EBNA1 plays several important roles in EBV latent infection and cellular transformation. It binds the same pocket as p53 in the HAUSP TRAF-like domain. Through interactions with p53, MDM2 and EBNA1, HAUSP plays a role in cell proliferation, apoptosis and EBV-mediated immortalization.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15230973   8 KFRWVIKNFSSLgSERVFSDIFVVGSCKWRLMAYPK----GVRDNRCFSLFLVVTDFKTLPcDWKRHTRLRLNVVNQLSE 83
Cdd:cd03772   4 TFSFTVERFSRL-SESVLSPPCFVRNLPWKIMVMPRnypdRNPHQKSVGFFLQCNAESDST-SWSCHAQAVLRIINYKDD 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 15230973  84 ELSILKETQMWFDQKTPAWGFLAMLPLTELKAENGGFLVN 123
Cdd:cd03772  82 EPSFSRRISHLFFSKENDWGFSNFMTWSEVTDPEKGFIED 121

Tripartite motif containing protein 37 (TRIM37) family, MATH domain; TRIM37 is a peroxisomal protein and is a member of the tripartite motif (TRIM) protein subfamily, also known as the RING-B-box-coiled-coil (RBCC) subfamily of zinc-finger proteins. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction and hepatomegaly. TRIM37, similar to other TRIMs, contains a cysteine-rich, zinc-binding RING-finger domain followed by another cysteine-rich zinc-binding domain, the B-box, and a coiled-coil domain. TRIM37 is autoubiquitinated in a RING domain-dependent manner, indicating that it functions as an ubiquitin E3 ligase. In addition to the tripartite motif, TRIM37 also contains a MATH domain C-terminal to the coiled-coil domain. The MATH domain of TRIM37 has been shown to interact with the TRAF domain of six known TRAFs in vitro, however, it is unclear whether this is physiologically relevant. Eleven TRIM37 mutations have been associated with Mulibrey nanism so far. One mutation, Gly322Val, is located in the MATH domain and is the only mutation that does not affect the length of the protein. It results in the incorrect subcellular localization of TRIM37.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15230973  12 VIKNFSSL--GSERVFSDIFVVGSCKWRLMAYP--KGVRDNRCFSLFLVVTdfKTLPCDWKRHTRLRLnvVNQLSEELSI 87
Cdd:cd03773  10 TLENFSTLrqSADPVYSDPLNVDGLCWRLKVYPdgNGEVRGNFLSVFLELC--SGLGEASKYEYRVEM--VHQANPTKNI 85

                        90       100       110
                ....*....|....*....|....*....|....
gi 15230973  88 LKETQMWFDQKTPaWGFLAMLPLTELKAEngGFL 121
Cdd:cd03773  86 KREFASDFEVGEC-WGYNRFFRLDLLINE--GYL 116