Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and similar proteins; TRAF5, also known as RING finger protein 84 (RNF84), is an important signal transducer for a wide range of TNF receptor superfamily members, including tumor necrosis factor receptor 1 (TNFR1), TNFR2, CD40, and other lymphocyte costimulatory receptors, RANK/TRANCE-R, ectodysplasin-A Receptor (EDAR), lymphotoxin-beta receptor (LT-betaR), latent membrane protein 1 (LMP1), and IRE1. It functions as an activator of NF-kappaB, MAPK, and JNK, and is involved in both RANKL- and TNFalpha-induced osteoclastogenesis. It mediates CD40 signaling by associating with the cytoplasmic tail of CD40. It also negatively regulates Toll-like receptor (TLR) signaling and functions as a negative regulator of the interleukin 6 (IL-6) receptor signaling pathway that limits the differentiation of inflammatory CD4(+) T cells. TRAF5 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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2168986047  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNSVPICPVDKEVIKPQEVF 94
Cdd:cd16642     1 LEDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLELNTTPICPIDKETIKSDEVF 56

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2168986047 185 ENSCPAYPVSCPNKC-VQTIPRAGVKEHL-TVCPEAEQDCPFKHYGCTVKGKRGNLQEH 241
Cdd:pfam02176   2 LETCPFFPIPCPNGCcKKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and similar proteins; TRAF5, also known as RING finger protein 84 (RNF84), is an important signal transducer for a wide range of TNF receptor superfamily members, including tumor necrosis factor receptor 1 (TNFR1), TNFR2, CD40, and other lymphocyte costimulatory receptors, RANK/TRANCE-R, ectodysplasin-A Receptor (EDAR), lymphotoxin-beta receptor (LT-betaR), latent membrane protein 1 (LMP1), and IRE1. It functions as an activator of NF-kappaB, MAPK, and JNK, and is involved in both RANKL- and TNFalpha-induced osteoclastogenesis. It mediates CD40 signaling by associating with the cytoplasmic tail of CD40. It also negatively regulates Toll-like receptor (TLR) signaling and functions as a negative regulator of the interleukin 6 (IL-6) receptor signaling pathway that limits the differentiation of inflammatory CD4(+) T cells. TRAF5 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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2168986047  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNSVPICPVDKEVIKPQEVF 94
Cdd:cd16642     1 LEDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLELNTTPICPIDKETIKSDEVF 56

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2168986047 185 ENSCPAYPVSCPNKC-VQTIPRAGVKEHL-TVCPEAEQDCPFKHYGCTVKGKRGNLQEH 241
Cdd:pfam02176   2 LETCPFFPIPCPNGCcKKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2168986047  40 EERYKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNSVPICPVDKEVIKPQEV 93
Cdd:COG5574   213 LADYKCFLCLEEPEVPSCTPCGHLFCLSCLLISWTKKKYEFCPLCRAKVYPKKV 266

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        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2168986047  30 DTEYQFVEQLEERYKCAFCHSVLHNPHQTGCGHRFCQHCIlsLRELNSVPICP 82
Cdd:TIGR00599  14 TTPIPSLYPLDTSLRCHICKDFFDVPVLTSCSHTFCSLCI--RRCLSNQPKCP 64

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 2168986047   45 CAFCHSV-LHNPHQTGCGHRFCQHCILSLRELNSV--PIC 81
Cdd:smart00184   1 CPICLEEyLKDPVILPCGHTFCRSCIRKWLESGNNtcPIC 40

Coiled-coil domain-containing protein 22; Human coiled-coil domain-containing protein 22 (CCDC22) is involved in regulation of NF-kappa-B signalling; the function may involve association with COMMD8 and a CUL1-dependent E3 ubiquitin ligase complex. It is part of the OMMD/CCDC22/CCDC93 (CCC) complex, which interacts with the multisubunit WASH complex required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. This entry also includes CCDC22 homologs from animals and plants.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 239 QEHERAALQDHMLLVLEKNFQLEQQ--ISDLYQSLEQKESKIQQLAGTVKKFEKELKQFTQmfgrngsflsnvqaltsht 316
Cdd:pfam05667 310 NEAPAATSSPPTKVETEEELQQQREeeLEELQEQLEDLESSIQELEKEIKKLESSIKQVEE------------------- 370

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2168986047 317 dksawlEAQVRQLLQIVNQQQSRLDLRsLVDAVDSVKQRITQL----EASDQRLVVLEGETNKH 376
Cdd:pfam05667 371 ------ELEELKEQNEELEKQYKVKKK-TLDLLPDAEENIAKLqalvDASAQRLVELAGQWEKH 427

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 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. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 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 2168986047 366 LVVLEGETNKHDAHINIHKAQLNKNEERFKLLEGACYSGKLIWKVTDYKAKKREAMEGHTVSVFSQPFYTSRCGYRLCAR 445
Cdd:cd03777     1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 446 AYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVTLMLLDQSGKKNHIVETFKADPNSSSFRRPDGEMNIASGCPRF 525
Cdd:cd03777    81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                         170       180
                  ....*....|....*....|....*...
gi 2168986047 526 VSHSTLESSrnTYIKDDTLFLKVAVDLT 553
Cdd:cd03777   161 VAQTVLENG--TYIKDDTIFIKVIVDTS 186

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 2168986047 386 QLNKNEERFKLLEGACYSGKLIWKVTDYKAKKREAMEGHTVSVFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVV 465
Cdd:cd03778     1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 466 MRGEFDSLLQWPFRQRVTLMLLDQSGKKnHIVETFKADPNSSSFRRPDGEMNIASGCPRFVSHSTLEsSRNTYIKDDTLF 545
Cdd:cd03778    81 MKGPNDALLRWPFNQKVTLMLLDQNNRE-HVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*E-AKNSYVRDDAIF 158

                  ....*.
gi 2168986047 546 LKVAVD 551
Cdd:cd03778   159 IKAIVD 164

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF4 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF4, including the Drosophila protein DTRAF1. 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. TRAF4 is highly expressed during embryogenesis, especially in the central and peripheral nervous system. Studies using TRAF4-deficient mice show that TRAF4 is required for neurogenesis, as well as the development of the trachea and the axial skeleton. In addition, TRAF4 augments nuclear factor-kappaB activation triggered by GITR (glucocorticoid-induced TNFR), a receptor expressed in T-cells, B-cells and macrophages. It also participates in counteracting the signaling mediated by Toll-like receptors through its association with TRAF6 and TRIF. DTRAF1 plays a pivotal role in the development of eye imaginal discs and photosensory neuron arrays in Drosophila. TRAF4 contains a RING finger domain, seven 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 2168986047 404 GKLIWKVTDYKAKKREAMEGHTVSVFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd03781     1 GTLLWKITDYSRKLQEAKGRDNLELFSPPFYTHRYGYKLQVSAFLNGNGSGEGSHLSVYIRVLPGEYDNLLEWPFSHRIT 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2168986047 484 LMLLDQS----GKKNHIVETFKADPNSSSFRRP----DGEMNIASGCPRFVSHSTLESsrNTYIKDDTLFLKVAVD 551
Cdd:cd03781    81 FTLLDQSdpslSKPQHITETFTPDPTWKNFQKPsasrLDESTLGFGYPKFISHEDLKK--RNYIKDDAIFLRASVE 154

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) and similar proteins; TRAF5, also known as RING finger protein 84 (RNF84), is an important signal transducer for a wide range of TNF receptor superfamily members, including tumor necrosis factor receptor 1 (TNFR1), TNFR2, CD40, and other lymphocyte costimulatory receptors, RANK/TRANCE-R, ectodysplasin-A Receptor (EDAR), lymphotoxin-beta receptor (LT-betaR), latent membrane protein 1 (LMP1), and IRE1. It functions as an activator of NF-kappaB, MAPK, and JNK, and is involved in both RANKL- and TNFalpha-induced osteoclastogenesis. It mediates CD40 signaling by associating with the cytoplasmic tail of CD40. It also negatively regulates Toll-like receptor (TLR) signaling and functions as a negative regulator of the interleukin 6 (IL-6) receptor signaling pathway that limits the differentiation of inflammatory CD4(+) T cells. TRAF5 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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2168986047  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNSVPICPVDKEVIKPQEVF 94
Cdd:cd16642     1 LEDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLELNTTPICPIDKETIKSDEVF 56

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 128 HLQHCSFQAVPCPNQSCREAMLRKDVKEHLSAYCRFREEKCLY----CKRDIVVTNLQDH 183
Cdd:pfam02176   1 HLETCPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2168986047 185 ENSCPAYPVSCPNKC-VQTIPRAGVKEHL-TVCPEAEQDCPFKHYGCTVKGKRGNLQEH 241
Cdd:pfam02176   2 LETCPFFPIPCPNGCcKKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

Meprin family, MATH domain; Meprins are multidomain, highly glycosylated extracellular metalloproteases, which are either anchored to the membrane or secreted into extracellular spaces. They are expressed in renal and intestinal brush border membranes, leukocytes, and cancer cells, and are capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. Meprin proteases are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. Despite their similarity, the two subunits differ in their ability to self-associate, in proteolytic processing during biosynthesis and in substrate specificity. Both subunits are synthesized as membrane spanning proteins, however, the alpha subunit is cleaved during biosynthesis and loses its transmembrane domain. Meprin beta forms homodimers or heterotetramers while meprin alpha oligomerizes into large complexes containing 10-100 subunits. 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 2168986047 407 IWKVTDYKAKKREAmeGHTVSVFSQPFYTSRcGYRLCARAYLNGdGSGKGTHLSLYFVVMRGEFDSLLQWP-FRQRVTLM 485
Cdd:cd03771     5 VWRVRNFSQLLETT--PKGTKIYSPRFYSPE-GYAFQVGLYPNG-TESYPGYTGLYFHLCSGENDDVLEWPcPNRQATMT 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 486 LLDQSGK-KNH---------------------------IVETFKADPNSSSFRRPDGemniaSGCPRFVSHSTLEsSRNt 537
Cdd:cd03771    81 LLDQDPDiQQRmsnqrsfttdpsmtssdngeyfwdrpsKVGSYDTDTNGCTCYRGPG-----YGWSTFISHSRLR-RRD- 153

                         170
                  ....*....|
gi 2168986047 538 YIK-DDTLFL 546
Cdd:cd03771   154 FLKgDDLIIL 163

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 2168986047  40 EERYKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNSVPICPVDKE 86
Cdd:cd23125     2 EEKYLCCNCKNVLKKAQQTLCGHRYCLACLSWIVRNNKNPICQKCKE 48

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 2168986047 407 IWKVTDYKakKREAMEGHTVSVFSQPFYTSRcGYRLCARAYLNGDGSGKGtHLSLYFVVMRGEFDSLLQWPFR-QRVTLM 485
Cdd:cd03782     5 IWHIRNFT--QLLATTPPNGKIYSPPFLSST-GYSFQVGLYLNGTDDYPG-NLAIYLHLTSGPNDDQLQWPCPwQQATMM 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 486 LLDQsgkKNHI-------------------------------VETFKADPNSSSFRRPDGemniaSGCPRFVSHSTLEsS 534
Cdd:cd03782    81 LLDQ---HPDIrqrmsnqrsvttdpnmtstdsdeyfwddprkVGSEVTDTDGSTFYRGPG-----YGTSAFITHLRLR-S 151

                         170
                  ....*....|...
gi 2168986047 535 RNtYIK-DDTLFL 546
Cdd:cd03782   152 RD-FIKgDDVIFL 163

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 2168986047  39 LEERYKCAFCHSVLHNPHQ-TGCGHRFCQHCILSLreLNSVPICPVDKEVIK 89
Cdd:cd23126     1 LDKKYECPVCCQVLRYPVQfEECGHRVCSSCLPEL--LRVEPRCPIDQGPID 50

RING finger, HC subclass, found in RING finger protein 125 (RNF125); RNF125, also known as T-cell RING activation protein 1 (TRAC-1), is an E3 ubiquitin-protein ligase that is predominantly expressed in lymphoid cells, and functions as a positive regulator of T cell activation. It also down-modulates HIV replication and inhibits pathogen-induced cytokine production. It negatively regulates type I interferon signaling, which conjugates Lys(48)-linked ubiquitination to retinoic acid-inducible gene-I (RIG-I) and subsequently leads to the proteasome-dependent degradation of RIG-I. Further, RNF125 conjugates ubiquitin to melanoma differentiation-associated gene 5 (MDA5), a family protein of RIG-I. It thus acts as a negative regulator of RIG-I signaling, and is a direct target of miR-15b in the context of Japanese encephalitis virus (JEV) infection. Moreover, RNF125 binds to and ubiquitinates JAK1, prompting its degradation and inhibition of receptor tyrosine kinase (RTK) expression. It also negatively regulates p53 function through physical interaction and ubiquitin-mediated proteasome degradation. Mutations in RNF125 may lead to overgrowth syndromes (OGS). RNF125, together with three closely related proteins: RNF114, RNF138 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM). The UIM of RNF125 binds K48-linked poly-ubiquitin chains and is, together with the RING domain, required for auto-ubiquitination.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2168986047  43 YKCAFCHSVLHNPHQTGCGHRFCQHCI-LSLRelNSVPICPV 83
Cdd:cd16542     2 FDCAVCLEVLHQPVRTRCGHVFCRPCIaTSLR--NNTWTCPY 41

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 2168986047  43 YKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNSVPiCPVD 84
Cdd:cd16449     1 LECPICLERLKDPVLLPCGHVFCRECIRRLLESGSIK-CPIC 41

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 2168986047  43 YKCAFCHSVLHNPHQTGCGHRFCQHCIL 70
Cdd:cd16718     5 FKCNLCNKVLEDPLTTPCGHVFCAGCVL 32

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        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2168986047  30 DTEYQFVEQLEERYKCAFCHSVLHNPHQTGCGHRFCQHCIlsLRELNSVPICP 82
Cdd:TIGR00599  14 TTPIPSLYPLDTSLRCHICKDFFDVPVLTSCSHTFCSLCI--RRCLSNQPKCP 64

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2168986047  38 QLEERYKCAFCHSVLHNPHQTGCGHRFCQHCIlsLRELNSVPICPVDKEviKPQEV 93
Cdd:COG5432    21 GLDSMLRCRICDCRISIPCETTCGHTFCSLCI--RRHLGTQPFCPVCRE--DPCES 72

Phage shock protein A [Transcription, Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 243 RAALQdhmllvlEKNfQLEQQISDLYQSLEQKESKIQQLAGTVKKFEKELKQFtqmfgRNGsfLSNVQAltshTDKSAwl 322
Cdd:COG1842    87 REALE-------RKA-ELEAQAEALEAQLAQLEEQVEKLKEALRQLESKLEEL-----KAK--KDTLKA----RAKAA-- 145

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 2168986047 323 EAQVRqllqiVNQQQSRLDLRSLVDAVDSVKQRITQLEA 361
Cdd:COG1842   146 KAQEK-----VNEALSGIDSDDATSALERMEEKIEEMEA 179

RING finger, HC subclass, found in peroxin-2 (PEX2) and similar proteins; PEX2, also known as peroxisome biogenesis factor 2, 35 kDa peroxisomal membrane protein, peroxisomal membrane protein 3, peroxisome assembly factor 1 (PAF-1), or RING finger protein 72 (RNF72), is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C-terminus. It may be involved in the biogenesis of peroxisomes, as well as in peroxisomal matrix protein import. Mutations in the PEX2 gene are the primary defect in a subset of patients with Zellweger syndrome and related peroxisome biogenesis disorders. Moreover, PEX2 functions as an E3-ubiquitin ligase that mediates the UBC4-dependent polyubiquitination of PEX5, a key player in peroxisomal matrix protein import, to control PEX5 receptor recycling or degradation.

                          10        20
                  ....*....|....*....|....*....
gi 2168986047  44 KCAFCHSV-LHNPHQTGCGHRFCQHCILS 71
Cdd:cd16526     3 ECAICGEWpTNNPYSTGCGHVYCYYCIKS 31

Uncharacterized N-terminal coiled-coil domain of peptidoglycan hydrolase CwlO [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 240 EHERAALQDHMLLVLEKNFQLEQQISDLYQSLEQKESKIQQLAGTVKKFEKELKQFTQMFGRNGSFLSNVQALTSHTDKS 319
Cdd:COG3883    36 QAELDALQAELEELNEEYNELQAELEALQAEIDKLQAEIAEAEAEIEERREELGERARALYRSGGSVSYLDVLLGSESFS 115

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 320 AWLEaQVRQLLQIVNQQQSRLDlrSLVDAVDSVKQRITQLEASDQRLVVLEGETNKHDAHINIHKAQLNK 389
Cdd:COG3883   116 DFLD-RLSALSKIADADADLLE--ELKADKAELEAKKAELEAKLAELEALKAELEAAKAELEAQQAEQEA 182

second RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the second RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2168986047  45 CAFCHSVLHNPHQTGCGHRFCQHCIlsLRELNSVPICPVDKEVI 88
Cdd:cd16514     4 CSLCLRLLYEPVTTPCGHTFCRACL--ERCLDHSPKCPLCRTSL 45

RING finger, HC subclass, found in tripartite motif-containing protein 35 (TRIM35) and similar proteins; TRIM35, also known as hemopoietic lineage switch protein 5 (HLS5), is a putative hepatocellular carcinoma (HCC) suppressor that inhibits phosphorylation of pyruvate kinase isoform M2 (PKM2), which is involved in aerobic glycolysis of cancer cells and further suppresses the Warburg effect and tumorigenicity in HCC. It also negatively regulates Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon production by suppressing the stability of interferon regulatory factor 7 (IRF7). Moreover, TRIM35 regulates erythroid differentiation by modulating globin transcription factor 1 (GATA-1) activity. TRIM35 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        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2168986047  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQHCILSLRELNSVPICPVDKEVIKPQE 92
Cdd:cd16599     1 FKEELLCPICYEPFREAVTLRCGHNFCKGCVSRSWERQPRAPCPVCKEASSSDD 54

Variant RING finger, HC subclass (C4C4-type), found in retinoblastoma-binding protein 6 (RBBP6) and similar proteins; RBBP6, also known as proliferation potential-related protein, protein P2P-R, retinoblastoma-binding Q protein 1 (RBQ-1), or p53-associated cellular protein of testis (PACT), is a nuclear E3 ubiquitin-protein ligase involved in multiple processes, such as the control of gene expression, mitosis, cell differentiation, and cell apoptosis. It plays a role in both promoting and inhibiting apoptosis in many human cancers, including esophageal, lung, hepatocellular, and colon cancers, familial myeloproliferative neoplasms, as well as in human immunodeficiency virus-associated nephropathy (HIVAN). It functions as an Rb- and p53-binding protein that plays an important role in chaperone-mediated ubiquitination and possibly in protein quality control. It acts as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in an increase of MDM2-mediated ubiquitination and degradation of p53/TP53, and leading to both apoptosis and cell growth. It is also a double-stranded RNA-binding protein that plays a role in mRNA processing by regulating the human polyadenylation machinery and modulating expression of mRNAs with AU-rich 3' untranslated regions (UTRs). Moreover, RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38 that negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Furthermore, RBBP6 is involved in tunicamycin-induced apoptosis by mediating protein kinase (PKR) activation. RBBP6 contains an N-terminal ubiquitin-like domain and a C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger. RBBP6 interacts with chaperones Hsp70 and Hsp40 through its N-terminal ubiquitin-like domain. It promotes the ubiquitination of p53 by Hdm2 in an E4-like manner through its RING finger. It also interacts directly with the pro-proliferative transcription factor Y-box-binding protein-1 (YB-1) via its RING finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2168986047  41 ERYKCAFCHSVLHNPHQTGC-GHRFCQHCILSLReLNSVPICPVDKEVIKP 90
Cdd:cd16620     2 DELKCPICKDLMKDAVLTPCcGNSFCDECIRTAL-LEEDFTCPTCKEPDVS 51

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 2168986047  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQHCIL---SLRELNSVPIC 81
Cdd:cd16608     3 LKDELLCSICLSIYQDPVSLGCEHYFCRQCITehwSRSEHRDCPEC 48

RING finger, HC subclass, found in Saccharomyces cerevisiae increased recombination centers protein 20 (IRC20) and similar proteins; IRC20 is an uncharacterized ATP-dependent helicase that is probably involved in a pathway contributing to genomic integrity. IRC20 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2168986047  43 YKCAFCHSVLHNPHQTGCGHRFCQHCILS-LRELNSVPIC 81
Cdd:cd23135     4 LSCSICFSEIRSGAILKCGHFFCLSCIASwLREKSTCPLC 43

RING finger, HC subclass, found in Saccharomyces cerevisiae radiation sensitivity protein 18 (RAD18) and similar proteins; RAD18, also called RING-type E3 ubiquitin transferase RAD18, acts as a postreplication repair E3 ubiquitin-protein ligase that associates with the E2 ubiquitin conjugating enzyme UBC2/RAD6 to form the UBC2-RAD18 ubiquitin ligase complex involved in postreplicative repair (PRR) of damaged DNA. The UBC2-RAD18 complex cooperates with RAD5 and the UBC13-MMS2 dimer to attach mono-ubiquitin chains on 'Lys-164' of POL30, which is necessary for PRR. The UBC2-RAD18 complex is also involved in prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine. RAD18 is an E3 RING-finger protein belonging to the UBC2/RAD6 epistasis group. It contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2168986047  44 KCAFCHSVLHNPHQTGCGHRFCQHCIlsLRELNSVPICPVDK 85
Cdd:cd23148     5 RCHICKDLLKAPMRTPCNHTFCSFCI--RTHLNNDARCPLCK 44

RING finger, HC subclass, found in constitutive photomorphogenesis protein 1 (COP1) and similar proteins; COP1, also known as RING finger and WD repeat domain protein 2 (RFWD2) or RING finger protein 200 (RNF200), is a central regulator of photomorphogenic development in plants, which targets key transcription factors for proteasome-dependent degradation. It is localized predominantly in the nucleus, but may also be present in the cytosol. Mammalian COP1 functions as an E3 ubiquitin-protein ligase that interacts with Jun transcription factors and modulates their transcriptional activity. It also interacts with and negatively regulates the tumor-suppressor protein p53. Moreover, COP1 associates with COP9 signalosome subunit 6 (CSN6), and is involved in 14-3-3sigma ubiquitin-mediated degradation. The CSN6-COP1 link enhances ubiquitin-mediated degradation of p27(Kip1), a critical CDK inhibitor involved in cell cycle regulation, to promote cancer cell growth. Furthermore, COP1 functions as the negative regulator of ETV1 and influences prognosis in triple-negative breast cancer. COP1 contains an N-terminal extension, a C3HC4-type RING-HC finger, a coiled coil domain, and seven WD40 repeats. In human COP1, a classic leucine-rich NES, and a novel bipartite NLS is bridged by the RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2168986047  43 YKCAFCHSVLHNPHQTGCGHRFCQHCIL-SLRELNSVPIC 81
Cdd:cd16504     3 FLCPICFDIIKEAFVTKCGHSFCYKCIVkHLEQKNRCPKC 42

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 2168986047 237 NLQEHERAALQDHMLLvLEKNFQLEQQISDLYQSLEQKESKIQQLAGTVKKFEKELKQFTqmfgrnGSFLSNVQALtshT 316
Cdd:TIGR04523 416 KLQQEKELLEKEIERL-KETIIKNNSEIKDLTNQDSVKELIIKNLDNTRESLETQLKVLS------RSINKIKQNL---E 485

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2168986047 317 DKSAWLEAQVRQLLQIvNQQQSRLD--LRSLVDAVDSVKQRITQLEAS----DQRLVVLEGETNKHDAHI---NIHKAQL 387
Cdd:TIGR04523 486 QKQKELKSKEKELKKL-NEEKKELEekVKDLTKKISSLKEKIEKLESEkkekESKISDLEDELNKDDFELkkeNLEKEID 564

                  ....*....
gi 2168986047 388 NKNEERFKL 396
Cdd:TIGR04523 565 EKNKEIEEL 573