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 49168598 404 GKLIWKVTDYKMKKREAVDGHTVSIFSQSFYTSRCGYRLCARAYLNGDGSGRGSHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd03780   1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 49168598 484 LMLLDQSGKKN-IMETFKPDPNSSSFKRPDGEMNIASGCPRFVAHSVLENAKNAYIKDDTLFLKVAVD 550
Cdd:cd03780  81 LMLLDQSGKKNhIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLENAKNTYIKDDTLFLKVAVD 148

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 49168598   183 HEENlCPEYPVFCPNNCA-KIILKTEVDEHL-AVCPEAEQDCPFKHYGCAVTDKRRNLQQH 241
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCkKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

Septal ring factor EnvC, activator of murein hydrolases AmiA and AmiB [Cell cycle control, cell division, chromosome partitioning];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 232 TDKRRNLQQHEHSALREHMRLVLEKNVQLEEQISDLHKSLEQKESKIQQLAETIKKLEKEFKQFAQLFGKNGS-----FL 306
Cdd:COG4942  46 LKKEEKALLKQLAALERRIAALARRIRALEQELAALEAELAELEKEIAELRAELEAQKEELAELLRALYRLGRqpplaLL 125

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 307 PNIQVFASHIDKSAWLEAQVHQLLQMVNQ-QQNKFDLRPLMEAVDTVKQKI-TLLENNDQRLAVLEEETNKHDTHINIHK 384
Cdd:COG4942 126 LSPEDFLDAVRRLQYLKYLAPARREQAEElRADLAELAALRAELEAERAELeALLAELEEERAALEALKAERQKLLARLE 205

                       170
                ....*....|....
gi 49168598 385 AQLSKNEERFKLLE 398
Cdd:COG4942 206 KELAELAAELAELQ 219

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF5 subfamily, TRAF domain, C-terminal MATH subdomain; 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. TRAF5 was identified as an activator of nuclear factor-kappaB and a regulator of lymphotoxin-beta receptor and CD40 signaling. Its interaction with CD40 is indirect, involving hetero-oligomerization with TRAF3. In addition, TRAF5 has been shown to associate with other TNFRs including CD27, CD30, OX40 and GITR (glucocorticoid-induced TNFR). It plays a role in modulating Th2 immune responses (driven by OX40 costimulation) and T-cell activation (triggered by GITR). It is also involved in osteoclastogenesis. TRAF5 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 49168598 404 GKLIWKVTDYKMKKREAVDGHTVSIFSQSFYTSRCGYRLCARAYLNGDGSGRGSHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd03780   1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 49168598 484 LMLLDQSGKKN-IMETFKPDPNSSSFKRPDGEMNIASGCPRFVAHSVLENAKNAYIKDDTLFLKVAVD 550
Cdd:cd03780  81 LMLLDQSGKKNhIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLENAKNTYIKDDTLFLKVAVD 148

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 49168598   183 HEENlCPEYPVFCPNNCA-KIILKTEVDEHL-AVCPEAEQDCPFKHYGCAVTDKRRNLQQH 241
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCkKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598    406 LIWKVTDY-KMKKREavdghtvSIFSQSFYtsRCGYRLCARAYLNGDgsgrgsHLSLYFVVMRGEFDSLlQWPFRQRVTL 484
Cdd:smart00061   2 LSHTFKNVsRLEEGE-------SYFSPSEE--HFNIPWRLKIYRKNG------FLSLYLHCEKEECDSR-KWSIEAEFTL 65

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 49168598    485 MLLDQSGKKnimetfKPDPNSSSFKRPDGemniaSGCPRFV 525
Cdd:smart00061  66 KLVSQNGKS------LSKKDKHVFEKPSG-----WGFSKFI 95

Septal ring factor EnvC, activator of murein hydrolases AmiA and AmiB [Cell cycle control, cell division, chromosome partitioning];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 232 TDKRRNLQQHEHSALREHMRLVLEKNVQLEEQISDLHKSLEQKESKIQQLAETIKKLEKEFKQFAQLFGKNGS-----FL 306
Cdd:COG4942  46 LKKEEKALLKQLAALERRIAALARRIRALEQELAALEAELAELEKEIAELRAELEAQKEELAELLRALYRLGRqpplaLL 125

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 307 PNIQVFASHIDKSAWLEAQVHQLLQMVNQ-QQNKFDLRPLMEAVDTVKQKI-TLLENNDQRLAVLEEETNKHDTHINIHK 384
Cdd:COG4942 126 LSPEDFLDAVRRLQYLKYLAPARREQAEElRADLAELAALRAELEAERAELeALLAELEEERAALEALKAERQKLLARLE 205

                       170
                ....*....|....
gi 49168598 385 AQLSKNEERFKLLE 398
Cdd:COG4942 206 KELAELAAELAELQ 219

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598   236 RNLQQHEHSALREHMRLvLEKNVQLEEQISDLHKSLEQKESKIQQLAETIKKLEKEFKQFAQLFGKNGSFLPNIQvfash 315
Cdd:TIGR04523 415 KKLQQEKELLEKEIERL-KETIIKNNSEIKDLTNQDSVKELIIKNLDNTRESLETQLKVLSRSINKIKQNLEQKQ----- 488

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598   316 idksAWLEAQVHQLLQMVNQQQNkfdlrpLMEAVDTVKQKITLLENN-----------DQRLAVLEEETNKHD---THIN 381
Cdd:TIGR04523 489 ----KELKSKEKELKKLNEEKKE------LEEKVKDLTKKISSLKEKieklesekkekESKISDLEDELNKDDfelKKEN 558

                         170
                  ....*....|....*
gi 49168598   382 IHKAQLSKNEERFKL 396
Cdd:TIGR04523 559 LEKEIDEKNKEIEEL 573

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 49168598    44 KCAFCHSVLHNPHQ-TGCGHRFCQHCIL-SLRELNTVPIC 81
Cdd:pfam13923   1 MCPICMDMLKDPSTtTPCGHVFCQDCILrALRAGNECPLC 40

chromosome partition protein MukB;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598   261 EEQISDLHKSLEQKESKIQQLAETIKKLEKEFKQFAQLFGKNGS--FLPNIQV-FASHIDKSAWLEAQVHQLLQMVNQQQ 337
Cdd:PRK04863  785 EKRIEQLRAEREELAERYATLSFDVQKLQRLHQAFSRFIGSHLAvaFEADPEAeLRQLNRRRVELERALADHESQEQQQR 864

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 49168598   338 NKFD-LRPLMEAVDTVKQKITLLENN--DQRLAVLEEE 372
Cdd:PRK04863  865 SQLEqAKEGLSALNRLLPRLNLLADEtlADRVEEIREQ 902

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF5 subfamily, TRAF domain, C-terminal MATH subdomain; 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. TRAF5 was identified as an activator of nuclear factor-kappaB and a regulator of lymphotoxin-beta receptor and CD40 signaling. Its interaction with CD40 is indirect, involving hetero-oligomerization with TRAF3. In addition, TRAF5 has been shown to associate with other TNFRs including CD27, CD30, OX40 and GITR (glucocorticoid-induced TNFR). It plays a role in modulating Th2 immune responses (driven by OX40 costimulation) and T-cell activation (triggered by GITR). It is also involved in osteoclastogenesis. TRAF5 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 49168598 404 GKLIWKVTDYKMKKREAVDGHTVSIFSQSFYTSRCGYRLCARAYLNGDGSGRGSHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd03780   1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 49168598 484 LMLLDQSGKKN-IMETFKPDPNSSSFKRPDGEMNIASGCPRFVAHSVLENAKNAYIKDDTLFLKVAVD 550
Cdd:cd03780  81 LMLLDQSGKKNhIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLENAKNTYIKDDTLFLKVAVD 148

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 49168598 404 GKLIWKVTDYKMKKREAVDGHTVSIFSQSFYTSRCGYRLCARAYLNGDGSGRGSHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd00270   1 GVLIWKIKDYSRKLQEAVAGSNTVLYSPPFYTSRYGYKLCLRLYLNGDGTGKGTHLSLFVHVMKGEYDALLEWPFRGKIT 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 49168598 484 LMLLDQSGK---KNIMETFKPDPNSSSF-KRPDGEMNIASGCPRFVAHSVLENakNAYIKDDTLFLKVAVD 550
Cdd:cd00270  81 LTLLDQSDDskrKHITETFMPDPNSSAFqRPPTGENNIGFGYPEFVPLEKLES--RGYVKDDTLFIKVEVD 149

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF1 subfamily, TRAF domain, C-terminal MATH subdomain; 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. TRAF1 expression is the most restricted among the TRAFs. It is found exclusively in activated lymphocytes, dendritic cells and certain epithelia. TRAF1 associates, directly or indirectly through heterodimerization with TRAF2, with the TNFR family receptors TNFR-2, CD30, RANK, CD40 and LMP1, among others. It also binds the intracellular proteins TRADD, TANK, TRIP, RIP1, RIP2 and FLIP. TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events. TRAF1 contains one zinc finger and one 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 49168598 404 GKLIWKVTDYKMKKREAVDGHTVSIFSQSFYTSRCGYRLCARAYLNGDGSGRGSHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd03779   1 GTFLWKITDVSQKQRESSHGRDVSLCSPAFYTAKYGYKVCLRLYLNGDGAGKGTHISLFFVIMKGEYDALLPWPFRHKVT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 49168598 484 LMLLDQSGKKNIMETFKPDPNSSSFKRPDGEMNIASGCPRFVAHSVLENAKNAYIKDDTLFLKVAVD 550
Cdd:cd03779  81 FMLLDQNNREHVIDAFRPDLSSASFQRPVSDMNVASGCPLFFPLKKLQSPKHAYCKDDTIYIKCVVD 147

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF6 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF6, including the Drosophila protein DTRAF2. 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. TRAF6 is the most divergent in its TRAF domain among the mammalian TRAFs. In addition to mediating TNFR family signaling, it is also an essential signaling molecule of the interleukin-1/Toll-like receptor superfamily. Whereas other TRAF molecules display similar and overlapping TNFR-binding specificities, TRAF6 binds completely different sites on receptors such as CD40 and RANK. TRAF6 serves as a molecular bridge between innate and adaptive immunity and plays a central role in osteoimmunology. DTRAF2, as an activator of nuclear factor-kappaB, plays a pivotal role in Drosophila development and innate immunity. TRAF6 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 49168598 404 GKLIWKVTDYKMKKREAVDGHTVSIFSQSFYTSRCGYRLCARAYLNGDGSGRGSHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd03776   1 GIYVWKIKNFSNLRRSMEAGSPVVIHSPGFYTSPPGYKLCARLNLSLPEARCPNYISLFVHLMQGENDSHLDWPFQGTIT 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 49168598 484 LMLLDQSGK-KNIMETFKPDPNSSSFKRPDGEMNIAS-GCPRFVAHSVLENAKnaYIKDDTLFLKVAV 549
Cdd:cd03776  81 LTLLDQSEPrQNIHETMMSKPELLAFQRPTTDRNPKGfGYVEFAHIEDLLQRG--FVKNDTLLIKIEV 146

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 49168598 404 GKLIWKVTDYKMKKREavdghtvSIFSQSFYtsRCGYRLCARAYLNGDGSgRGSHLSLYFVVMRGEFDSLlQWPFRQRVT 483
Cdd:cd00121   1 GKHTWKIVNFSELEGE-------SIYSPPFE--VGGYKWRIRIYPNGDGE-SGDYLSLYLELDKGESDLE-KWSVRAEFT 69

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 49168598 484 LMLLDQSGKKNIMETFKPDPNSssfkrpdgEMNIASGCPRFVAHSVLEnaKNAYIKDDTLFLKVAVD 550
Cdd:cd00121  70 LKLVNQNGGKSLSKSFTHVFFS--------EKGSGWGFPKFISWDDLE--DSYYLVDDSLTIEVEVK 126

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and similar proteins; TRAF6, also known as interleukin-1 signal transducer or RING finger protein 85 (RNF85), is a cytoplasmic adapter protein that mediates signals induced by the tumor necrosis factor receptor (TNFR) superfamily and Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) family. It functions as a mediator involved in the activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and interferon regulatory factor pathways, as well as in IL-1R-mediated activation of NF-kappaB. TRAF6 is also an oncogene that plays a vital role in K-RAS-mediated oncogenesis. TRAF6 contains an N-terminal domain with a modified C3HC3D-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598  42 RYKCAFCHSVLHNPHQTGCGHRFCQHCIL-SLRElnTVPICPVDKEVIKSQEVFKDNCCK 100
Cdd:cd16643   1 KYECPICLMALREPVQTPCGHRFCKACILkSIRE--AGHKCPVDNEPLLENQLFPDNFAK 58

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598    406 LIWKVTDY-KMKKREavdghtvSIFSQSFYtsRCGYRLCARAYLNGDgsgrgsHLSLYFVVMRGEFDSLlQWPFRQRVTL 484
Cdd:smart00061   2 LSHTFKNVsRLEEGE-------SYFSPSEE--HFNIPWRLKIYRKNG------FLSLYLHCEKEECDSR-KWSIEAEFTL 65

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 49168598    485 MLLDQSGKKnimetfKPDPNSSSFKRPDGemniaSGCPRFV 525
Cdd:smart00061  66 KLVSQNGKS------LSKKDKHVFEKPSG-----WGFSKFI 95

RING finger, HC subclass, found in tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1)-like and similar proteins; TRAF1, also known as Epstein-Barr virus-induced protein 6 (EBI6), is an adapter molecule that regulates the activation of NF-kappa-B and JNK. It plays a role in the regulation of cell survival and apoptosis. The heterotrimer formed by TRAF1 and TRAF2 is part of an E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14. The TRAF1/TRAF2 complex recruits the antiapoptotic E3 protein-ubiquitin ligases BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This subfamily corresponds a group of TRAF1-like proteins that contains an N-terminal domain with a typical C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 49168598  40 EERYKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNTVPICPVDKE 86
Cdd:cd23125   2 EEKYLCCNCKNVLKKAQQTLCGHRYCLACLSWIVRNNKNPICQKCKE 48

Modified RING finger, HC subclass (C3HC3D-type), found in uncharacterized proteins similar to tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4); This subfamily corresponds to a group of uncharacterized proteins that shows high sequence similarity with tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4). TRAF4, also known as cysteine-rich domain associated with RING and Traf domains protein 1, or metastatic lymph node gene 62 protein (MLN 62), or RING finger protein 83 (RNF83), is a member of TRAF protein family, which mainly function in the immune system, where they mediate signaling through tumor necrosis factor receptors (TNFRs) and interleukin-1/Toll-like receptors (IL-1/TLRs). It also plays a critical role in the nervous system, as well as in carcinogenesis. Like TRAF4, members of this subfamily contain a modified C3HC3D-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 49168598  39 LEERYKCAFCHSVLHNPHQ-TGCGHRFCQHCILSLreLNTVPICPVDKEVIK 89
Cdd:cd23126   1 LDKKYECPVCCQVLRYPVQfEECGHRVCSSCLPEL--LRVEPRCPIDQGPID 50

Meprin family, Alpha subunit, MATH domain; Meprins are multidomain extracellular metalloproteases capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. They are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. The alpha subunit is synthesized as a membrane spanning protein, however, it is cleaved during biosynthesis and loses its transmembrane domain. It oligomerizes into large complexes, containing 10-100 subunits (dimers that associate noncovalently), which are secreted as latent proteases and can move through extracellular spaces in a nondestructive manner. This allows delivery of the concentrated protease to sites containing activating enzymes, such as sites of inflammation, infection or cancerous growth. Meprin alpha shows preference for small or hydrophobic residues at the P1 and P1' sites of its substrate. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 401 CYNGklIWKVTDYKmKKREAVDGHTVsIFSQSFYTSRcGYRLCARAY-LNGDGSGRGSHLSLYFVVMRGEFDSLLQWPFR 479
Cdd:cd03783   1 CPNA--VWRVRNFS-QILENTTKGDV-LQSPRFYSPE-GYGYGVSLYpLSNESDYSGNYTGLYFHLCSGENDAVLEWPAL 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 480 QR-VTLMLLDQSGK-KNIMET---FKPDPNSSS--------FKRPD--GEMNIASGCPR--------FVAHSVLEnaKNA 536
Cdd:cd03783  76 NRqAIITVLDQDPDvRLRMSSsrsFTTDKSQTSsaingtlrWDRPSrvGTYDTSCDCFRgidfgwstFISHSQLR--RRS 153

                       170
                ....*....|.
gi 49168598 537 YIKDDTLFLKV 547
Cdd:cd03783 154 FLKNDDLIIFV 164

Meprin family, Beta subunit, MATH domain; Meprins are multidomain extracellular metalloproteases capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. They are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. The beta subunit is a type I membrane protein, which forms homodimers or heterotetramers (alpha2beta2 or alpha3beta). Meprin beta shows preference for acidic residues at the P1 and P1' sites of its substrate. Among its best substrates are growth factors and chemokines such as gastrin and osteopontin. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 407 IWKVTDYKmkKREAVDGHTVSIFSQSFYTSRcGYRLCARAYLNGDGSGRGsHLSLYFVVMRGEFDSLLQWPFR-QRVTLM 485
Cdd:cd03782   5 IWHIRNFT--QLLATTPPNGKIYSPPFLSST-GYSFQVGLYLNGTDDYPG-NLAIYLHLTSGPNDDQLQWPCPwQQATMM 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 486 LLDQ--------SGKKNIM-----------ETFKPDPNS--SSFKRPDGEMNI---ASGCPRFVAHSVLENakNAYIK-D 540
Cdd:cd03782  81 LLDQhpdirqrmSNQRSVTtdpnmtstdsdEYFWDDPRKvgSEVTDTDGSTFYrgpGYGTSAFITHLRLRS--RDFIKgD 158

                ....*
gi 49168598 541 DTLFL 545
Cdd:cd03782 159 DVIFL 163

RING finger, HC subclass, found in ligand of numb protein X 3 (LNX3); LNX3, also known as PDZ domain-containing RING finger protein 3 (PDZRN3), or Semaphorin cytoplasmic domain-associated protein 3 (SEMACAP3), is an E3 ubiquitin-protein ligase that was first identified as a Semaphorin-binding partner. It is also responsible for the ubiquitination and degradation of Numb, a component of the Notch signaling pathway that functions in the specification of cell fates during development and is known to control cell numbers during neurogenesis in vertebrates. LNX3 acts as a negative regulator of osteoblast differentiation by inhibiting Wnt-beta-catenin signaling. LNX3 also plays an important role in neuromuscular junction formation. It interacts with and ubiquitinates the muscle specific tyrosine kinase (MuSK), thus promoting its endocytosis and negatively regulating the cell surface expression of this key regulator of postsynaptic assembly. LNX3 contains an N-terminal C3HC4-type RING-HC finger, two PDZ domains, and a C-terminal LNX3 homology (LNX3H) domain.

                        10        20
                ....*....|....*....|....*...
gi 49168598  43 YKCAFCHSVLHNPHQTGCGHRFCQHCIL 70
Cdd:cd16718   5 FKCNLCNKVLEDPLTTPCGHVFCAGCVL 32

HC subclass of RING (RING-HC) finger and its variants; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers. Some have a different Cys/His pattern. Some lack a single Cys or His residue at typical Zn ligand positions, especially, the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can chelate Zn in a RING finger as well. This family corresponds to the HC subclass of RING (RING-HC) fingers that are characterized by containing C3HC4-type canonical RING-HC fingers or noncanonical RING-HC finger variants, including C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type modified RING-HC fingers. The canonical RING-HC finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-HC fingers can be found in a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle, and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enables efficient transfer of ubiquitin from E2 to the substrates.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 49168598  43 YKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNTVPiCPVD 84
Cdd:cd16449   1 LECPICLERLKDPVLLPCGHVFCRECIRRLLESGSIK-CPIC 41

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 49168598    39 LEERYKCAFCHSVLHNPHQTGCGHRFCQHCIlsLRELNTVPICP 82
Cdd:TIGR00599  23 LDTSLRCHICKDFFDVPVLTSCSHTFCSLCI--RRCLSNQPKCP 64

RING finger, HC subclass, found in ligand of Numb protein LNX3, LNX4, and similar proteins; The ligand of Numb protein X (LNX) family, also known as PDZ and RING (PDZRN) family, includes LNX1-5, which can interact with Numb, a key regulator of neurogenesis and neuronal differentiation. LNX5 (also known as PDZK4, or PDZRN4L) shows high sequence homology to LNX3 and LNX4, but it lacks the RING domain. LNX1-4 proteins function as E3 ubiquitin ligases and have a unique domain architecture consisting of an N-terminal RING-HC finger for E3 ubiquitin ligase activity and either two or four PDZ domains necessary for the substrate-binding. This family corresponds to LNX3/LNX4-like proteins, which contains a C3HC4-type RING-HC finger and two PDZ domains.

                        10        20
                ....*....|....*....|....*..
gi 49168598  44 KCAFCHSVLHNPHQTGCGHRFCQHCIL 70
Cdd:cd16512   2 KCKLCLGVLEEPLATPCGHVFCAGCVL 28

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 49168598  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQHCIlsLRELNTVPICPV 83
Cdd:COG5432  22 LDSMLRCRICDCRISIPCETTCGHTFCSLCI--RRHLGTQPFCPV 64

RING finger, HC subclass, found in peroxin-10 (PEX10) and similar proteins; PEX10, also known as peroxisome biogenesis factor 10, peroxisomal biogenesis factor 10, peroxisome assembly protein 10, or RING finger protein 69 (RNF69), is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C-terminus. It plays an essential role in peroxisome assembly, import of target substrates, and recycling or degradation of protein complexes and amino acids. It is an essential component of the spinal locomotor circuit, and thus its mutations may be involved in peroxisomal biogenesis disorders (PBD). Mutations in human PEX10 also result in autosomal recessive ataxia. Moreover, PEX10 functions as an E3-ubiquitin ligase with an E2, UBCH5C. It mono- or poly-ubiquitinates PEX5, a key player in peroxisomal matrix protein import, in a UBC4-dependent manner, to control PEX5 receptor recycling or degradation. It also links the E2 ubiquitin conjugating enzyme PEX4 to the protein import machinery of the peroxisome.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 49168598  44 KCAFCHSVLHNPHQTGCGHRFCQHCILSLreLNTVPICPVDKEVIKSQEV 93
Cdd:cd16527   2 KCSLCLEERRHPTATPCGHLFCWSCITEW--CNEKPECPLCREPFQPQRL 49

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598   236 RNLQQHEHSALREHMRLvLEKNVQLEEQISDLHKSLEQKESKIQQLAETIKKLEKEFKQFAQLFGKNGSFLPNIQvfash 315
Cdd:TIGR04523 415 KKLQQEKELLEKEIERL-KETIIKNNSEIKDLTNQDSVKELIIKNLDNTRESLETQLKVLSRSINKIKQNLEQKQ----- 488

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598   316 idksAWLEAQVHQLLQMVNQQQNkfdlrpLMEAVDTVKQKITLLENN-----------DQRLAVLEEETNKHD---THIN 381
Cdd:TIGR04523 489 ----KELKSKEKELKKLNEEKKE------LEEKVKDLTKKISSLKEKieklesekkekESKISDLEDELNKDDfelKKEN 558

                         170
                  ....*....|....*
gi 49168598   382 IHKAQLSKNEERFKL 396
Cdd:TIGR04523 559 LEKEIDEKNKEIEEL 573

RING finger, HC subclass, found in tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and similar proteins; TRAF2, also known as tumor necrosis factor type 2 receptor-associated protein 3, is an E3 ubiquitin-protein ligase that was identified as a 75 kDa tumor necrosis factor receptor (TNF-R2)-associated signaling protein. It interacts with members of the TNF receptor superfamily and connects the receptors to downstream signaling proteins. It also mediates K63-linked polyubiquitination of RIP1, a kinase pivotal in TNFalpha-induced NF-kappaB activation. Moreover, TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15. It also acts as an important biological suppressor of necroptosis. It inhibits TNF-related apoptosis inducing ligand (TRAIL)- and CD95L-induced apoptosis and necroptosis. TRAF2 contains an N-terminal domain with a typical C3HC4-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

                        10        20
                ....*....|....*....|....*...
gi 49168598  42 RYKCAFCHSVLHNPHQTGCGHRFCQHCI 69
Cdd:cd16639   1 KYLCSDCRNILRRPFQAQCGHRYCSYCL 28

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 49168598     45 CAFCHSV-LHNPHQTGCGHRFCQHCILSLRELNTV--PIC 81
Cdd:smart00184   1 CPICLEEyLKDPVILPCGHTFCRSCIRKWLESGNNtcPIC 40

RING finger, HC subclass, found in tripartite motif-containing protein 62 (TRIM62) and similar proteins; TRIM62, also known as Ductal Epithelium Associated Ring Chromosome 1 (DEAR1), is a cytoplasmic E3 ubiquitin-protein ligase that was identified as a dominant regulator of acinar morphogenesis in the mammary gland. It is implicated in the inflammatory response of immune cells by regulating the Toll-like receptor 4 (TLR4) signaling pathway, leading to increased activity of the activator protein 1 (AP-1) transcription factor in primary macrophages. It is also involved in muscular protein homeostasis, especially during inflammation-induced atrophy, and may play a role in the pathogenesis of ICU-acquired weakness (ICUAW) by activating and maintaining inflammation in myocytes. Moreover, TRIM62 facilitates K27-linked poly-ubiquitination of CARD9 and also regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. It also functions as a chromosome 1p35 tumor suppressor and negatively regulates transforming growth factor beta (TGFbeta)-driven epithelial-mesenchymal transition (EMT) by binding to and promoting the ubiquitination of SMAD3, a major effector of TGFbeta-mediated EMT. TRIM62 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 49168598  38 RLEERYKCAFCHSVLHNPHQTGCGHRFCQHCIL---SLRELNTVPIC 81
Cdd:cd16608   2 SLKDELLCSICLSIYQDPVSLGCEHYFCRQCITehwSRSEHRDCPEC 48

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 49168598    44 KCAFCHSVLHNPHQ-TGCGHRFCQHCIL-SLRELNTVPIC 81
Cdd:pfam13923   1 MCPICMDMLKDPSTtTPCGHVFCQDCILrALRAGNECPLC 40

Uncharacterized protein, contains DUF3084 domain [Function unknown];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49168598 244 SALREHMRLVLEKNVQLEEQISDLHKSLEQKESKIQQLAETIKKLEKEFKQFAQlfgkngsflpNIQVFASHIDKSAWLE 323
Cdd:COG4372  27 AALSEQLRKALFELDKLQEELEQLREELEQAREELEQLEEELEQARSELEQLEE----------ELEELNEQLQAAQAEL 96

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 49168598 324 AQVHQLLQMVNQQQNKfdlrpLMEAVDTVKQKITLLEnndQRLAVLEEETNKHDTHINIHKAQLSKNEERFKLLE 398
Cdd:COG4372  97 AQAQEELESLQEEAEE-----LQEELEELQKERQDLE---QQRKQLEAQIAELQSEIAEREEELKELEEQLESLQ 163

second RING finger, HC subclass, found in Arabidopsis thaliana ORTHRUS and similar proteins; This subfamily includes Arabidopsis thaliana ORTHRUS 1-5. They are E3 ubiquitin-protein ligases that may participate in CpG methylation-dependent transcriptional regulation and/or epigenetic transcriptional silencing. ORTHRUS 1 mediates ubiquitination with the E2 ubiquitin-conjugating enzymes UBC11, UBC8 and UBC8 homologs (e.g. UBC10, UBC11, UBC28 and UBC29) but not with UBC27, UBC30, UBC32, UBC34 and UBC36. ORTHRUS 2 and 5 mediate ubiquitination with the E2 ubiquitin-conjugating enzyme UBC11. ORTHRUS 1 and 2 promote methylation-mediated gene silencing leading, for example, to early flowering. They can bind to CpG, CpNpG, and CpNpN DNA motifs, with a strong preference for methylated forms, and with highest affinity for CpG substrates. Members of this subfamily contain two typical C3HC4-type RING-HC fingers. This model corresponds to the second one.

                        10        20        30
                ....*....|....*....|....*....|..
gi 49168598  38 RLEERYKCAFCHSVLHNPHQTGCGHRFCQHCI 69
Cdd:cd23139   1 RLLKEFGCQICKKVLSLPVSTPCGHNFCKACL 32

RING finger, HC subclass, found in ligand of numb protein X 4 (LNX4); LNX4, also known as PDZ domain-containing RING finger protein 4 (PDZRN4), or SEMACAP3-like protein (SEMCAP3L), is an E3 ubiquitin-protein ligase responsible for the ubiquitination and degradation of Numb, a component of the Notch signaling pathway that functions in the specification of cell fates during development and is known to control cell numbers during neurogenesis in vertebrates. LNX4 contains an N-terminal C3HC4-type RING-HC finger, two PDZ domains, and a C-terminal LNX3 homology (LNX3H) domain.

                        10        20
                ....*....|....*....|....*..
gi 49168598  44 KCAFCHSVLHNPHQTGCGHRFCQHCIL 70
Cdd:cd16719   6 KCKLCGKVLEEPLSTPCGHVFCAGCLL 32