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 15232931  82 TYCLKIESFIKfatsPNAEKYESRPFESGGYNWTLIVYPKGNIKEGaplNYVSMYVQIDNSTLLNSPKEVYAEVKFFIYN 161
Cdd:cd00121   2 KHTWKIVNFSE----LEGESIYSPPFEVGGYKWRIRIYPNGDGESG---DYLSLYLELDKGESDLEKWSVRAEFTLKLVN 74

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 15232931 162 RKEDKYLTYQETDaKRFFLFKPYWGYGNVRPYTDVANPNagwLFDGDNVLFGVDV 216
Cdd:cd00121  75 QNGGKSLSKSFTH-VFFSEKGSGWGFPKFISWDDLEDSY---YLVDDSLTIEVEV 125

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 15232931  82 TYCLKIESFIKfatsPNAEKYESRPFESGGYNWTLIVYPKGNIKEGaplNYVSMYVQIDNSTLLNSPKEVYAEVKFFIYN 161
Cdd:cd00121   2 KHTWKIVNFSE----LEGESIYSPPFEVGGYKWRIRIYPNGDGESG---DYLSLYLELDKGESDLEKWSVRAEFTLKLVN 74

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 15232931 162 RKEDKYLTYQETDaKRFFLFKPYWGYGNVRPYTDVANPNagwLFDGDNVLFGVDV 216
Cdd:cd00121  75 QNGGKSLSKSFTH-VFFSEKGSGWGFPKFISWDDLEDSY---YLVDDSLTIEVEV 125

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 15232931   244 PNFSSLEK-QYYVSDKFVIGGRSWALKVYPSGDgegqGNSLSLYVVAVDVKPYD-KIYLKAKLRIINQrDSKHMEKKVES 321
Cdd:pfam00917   2 KNFSKIKEgESYYSPVEERFNIPWRLQIYRKGG----FLGLYLHCDKEEELERGwSIETEFTLKLVSS-NGKSVTKTDTH 76

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 15232931   322 WSDQANSWGFQKFVPFADLKdtsKGLLVNDTLKMEIE 358
Cdd:pfam00917  77 VFEKPKGWGWGKFISWDDLE---KDYLVDDSITVEAH 110

Ubiquitin carboxyl-terminal hydrolase [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15232931   99 AEKYESRPFESGGYNWTLIVYPKGNIKEGaplnyVSMYVQIDNSTL-LNSPKEVYAEVKF-FIYNRKEDKYLTYQETDAK 176
Cdd:COG5077   52 AKKVESPPFSVGGHTWKIILFPQGNNQCN-----VSVYLEYEPQELeETGGKYYDCCAQFaFDISNPKYPTIEYINKSHH 126

                         90       100
                 ....*....|....*....|....*.
gi 15232931  177 RFFLFKPYWGYGNVRPYTDVANPNAG 202
Cdd:COG5077  127 RFSMESTDWGFTNFIDLNKLIEPSPG 152

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 15232931  82 TYCLKIESFIKfatsPNAEKYESRPFESGGYNWTLIVYPKGNIKEGaplNYVSMYVQIDNSTLLNSPKEVYAEVKFFIYN 161
Cdd:cd00121   2 KHTWKIVNFSE----LEGESIYSPPFEVGGYKWRIRIYPNGDGESG---DYLSLYLELDKGESDLEKWSVRAEFTLKLVN 74

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 15232931 162 RKEDKYLTYQETDaKRFFLFKPYWGYGNVRPYTDVANPNagwLFDGDNVLFGVDV 216
Cdd:cd00121  75 QNGGKSLSKSFTH-VFFSEKGSGWGFPKFISWDDLEDSY---YLVDDSLTIEVEV 125

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
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 15232931 299 YLKAKLRIINQRDS-KHMEKKVE-SWSDQANSWGFQKFVPFADLKDTSKGLLVNDTLKMEIEF 359
Cdd:cd03772  68 HAQAVLRIINYKDDePSFSRRIShLFFSKENDWGFSNFMTWSEVTDPEKGFIEDDTITLEVYV 130

Speckle-type POZ protein (SPOP) family, MATH domain; composed of proteins with similarity to human SPOP. SPOP was isolated as a novel antigen recognized by serum from a scleroderma patient, whose overexpression in COS cells results in a discrete speckled pattern in the nuclei. It contains an N-terminal MATH domain and a C-terminal BTB (also called POZ) domain. Together with Cul3, SPOP constitutes an ubiquitin E3 ligase which is able to ubiquitinate the PcG protein BMI1, the variant histone macroH2A1 and the death domain-associated protein Daxx. Therefore, SPOP may be involved in the regulation of these proteins and may play a role in transcriptional regulation, apoptosis and X-chromosome inactivation. Cul3 binds to the BTB domain of SPOP whereas Daxx and the macroH2A1 nonhistone region have been shown to bind to the MATH domain. Both MATH and BTB domains are necessary for the nuclear speckled accumulation of SPOP. There are many proteins, mostly uncharacterized, containing both MATH and BTB domains from C. elegans and plants which are excluded from this family.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15232931 100 EKYESRPFESGGYN----WTLIVYPKGNIKEGAplNYVSMYVqidnsTLLNSPK-EVYAEVKFFIYNRKEDKYLTYQETD 174
Cdd:cd03774  22 GEVIKSSTFSSGANdklkWCLRVNPKGLDEESK--DYLSLYL-----LLVSCPKsEVRAKFKFSILNAKGEETKAMESQR 94

                        90
                ....*....|...
gi 15232931 175 AKRFFLFKPyWGY 187
Cdd:cd03774  95 AYRFVQGKD-WGF 106

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 15232931   244 PNFSSLEK-QYYVSDKFVIGGRSWALKVYPSGDgegqGNSLSLYVVAVDVKPYD-KIYLKAKLRIINQrDSKHMEKKVES 321
Cdd:pfam00917   2 KNFSKIKEgESYYSPVEERFNIPWRLQIYRKGG----FLGLYLHCDKEEELERGwSIETEFTLKLVSS-NGKSVTKTDTH 76

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 15232931   322 WSDQANSWGFQKFVPFADLKdtsKGLLVNDTLKMEIE 358
Cdd:pfam00917  77 VFEKPKGWGWGKFISWDDLE---KDYLVDDSITVEAH 110

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link cell surface TNFRs and receptors of the interleukin-1/Toll-like family to downstream kinase signaling 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. There are at least six mammalian and three Drosophila proteins containing TRAF domains. The mammalian TRAFs display varying expression profiles, indicating independent and cell type-specific regulation. They display distinct, as well as overlapping functions and interactions with receptors. Most TRAFs, except TRAF1, share N-terminal homology and contain a RING domain, multiple zinc finger domains, and a TRAF domain. TRAFs form homo- and heterotrimers through its TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15232931 268 LKVYPSGDGEGQGNSLSLYVVaVDVKPYDKIY-----LKAKLRIINQRD-------SKHMEKKVESWSDQAN-------S 328
Cdd:cd00270  41 LRLYLNGDGTGKGTHLSLFVH-VMKGEYDALLewpfrGKITLTLLDQSDdskrkhiTETFMPDPNSSAFQRPptgenniG 119

                        90       100       110
                ....*....|....*....|....*....|
gi 15232931 329 WGFQKFVPFADLKdtSKGLLVNDTLKMEIE 358
Cdd:cd00270 120 FGYPEFVPLEKLE--SRGYVKDDTLFIKVE 147

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF2 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF2 associates with the receptors TNFR-1, TNFR-2, RANK (which mediates differentiation and maturation of osteoclasts) and CD40 (which is important for the proliferation and activation of B cells), among others. It regulates distinct pathways that lead to the activation of nuclear factor-kappaB and Jun NH2-terminal kinases. TRAF2 also indirectly associates with death receptors through its interaction with TRADD (TNFR-associated death domain protein). It is involved in regulating oxidative stress or ROS-induced cell death and in the preconditioning of cells by sublethal stress for protection from subsequent injury. TRAF2 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15232931 233 SLHDRLYKWTLPNFSSLEKQY------------YVSDKFvigGRSWALKVYPSGDGEGQGNSLSLYVVAVDvKPYDKIY- 299
Cdd:cd03778  15 STYDGVFIWKISDFARKRQEAvagripaifspaFYTSRY---GYKMCLRIYLNGDGTGRGTHLSLFFVVMK-GPNDALLr 90

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 15232931 300 ----LKAKLRIINQRDSKHMekkVESWSDQANSWGFQKfvPFADLKDTS 344
Cdd:cd03778  91 wpfnQKVTLMLLDQNNREHV---IDAFRPDVTSSSFQR--PVNDMNIAS 134

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15232931     85 LKIESFIKFATSPNAEKYESRPFESGGYNWTLIVYPKGnikegaplNYVSMYVQIDNSTLLNSPKEVYAEVKFFIYNRKE 164
Cdd:smart00061   1 VLSHTFKNVSRLEEGESYFSPSEEHFNIPWRLKIYRKN--------GFLSLYLHCEKEECDSRKWSIEAEFTLKLVSQNG 72

                           90       100
                   ....*....|....*....|....*
gi 15232931    165 DKYLTYQETDakrfFLFKPYWGYGN 189
Cdd:smart00061  73 KSLSKKDKHV----FEKPSGWGFSK 93