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 31543889 308 GVLIWKIGSYGRRLQEAKAKPNLECFSPAFYTHKYGYKLQVSAFLNGNGSGEGTHLSIYIRVLPGAFDNLLEWPFARRVT 387
Cdd:cd03781   1 GTLLWKITDYSRKLQEAKGRDNLELFSPPFYTHRYGYKLQVSAFLNGNGSGEGSHLSVYIRVLPGEYDNLLEWPFSHRIT 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 31543889 388 FSLLDQSDPGLAKPQHVTETFHPDPNWKNFQKPGTWRgsLDESSLGFGYPKFISHQDIRKRNYVRDDAVFIRASVE 463
Cdd:cd03781  81 FTLLDQSDPSLSKPQHITETFTPDPTWKNFQKPSASR--LDESTLGFGYPKFISHEDLKKRNYIKDDAIFLRASVE 154

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 31543889   210 HQYQCPRLPVPCPNQCGVGTVAREDLPTHLKDSCSTAFVLCPFKESGCKHRCPKLAMGRH 269
Cdd:pfam02176   1 HLETCPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFKVFGCKEDVKREALQRH 60

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 31543889 308 GVLIWKIGSYGRRLQEAKAKPNLECFSPAFYTHKYGYKLQVSAFLNGNGSGEGTHLSIYIRVLPGAFDNLLEWPFARRVT 387
Cdd:cd03781   1 GTLLWKITDYSRKLQEAKGRDNLELFSPPFYTHRYGYKLQVSAFLNGNGSGEGSHLSVYIRVLPGEYDNLLEWPFSHRIT 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 31543889 388 FSLLDQSDPGLAKPQHVTETFHPDPNWKNFQKPGTWRgsLDESSLGFGYPKFISHQDIRKRNYVRDDAVFIRASVE 463
Cdd:cd03781  81 FTLLDQSDPSLSKPQHITETFTPDPTWKNFQKPSASR--LDESTLGFGYPKFISHEDLKKRNYIKDDAIFLRASVE 154

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 31543889   210 HQYQCPRLPVPCPNQCGVGTVAREDLPTHLKDSCSTAFVLCPFKESGCKHRCPKLAMGRH 269
Cdd:pfam02176   1 HLETCPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFKVFGCKEDVKREALQRH 60

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31543889    327 KPNLECFSPAFYTHKYGYKLQVSaflngngsGEGTHLSIYIRVLPGAFDNLlEWPFARRVTFSLLDQSDPglakpqhvte 406
Cdd:smart00061  13 EEGESYFSPSEEHFNIPWRLKIY--------RKNGFLSLYLHCEKEECDSR-KWSIEAEFTLKLVSQNGK---------- 73

                           90       100       110
                   ....*....|....*....|....*....|....
gi 31543889    407 tFHPDPNWKNFQKPGTWrgsldesslgfGYPKFI 440
Cdd:smart00061  74 -SLSKKDKHVFEKPSGW-----------GFSKFI 95

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
                   ....*....|....*....|....*....|....*...
gi 31543889     18 CPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCP 55
Cdd:smart00184   1 CPICLEEYLKDPVILPCGHTFCRSCIRKWLESGNNTCP 38

CDK-activating kinase assembly factor MAT1; All proteins in this family for which functions are known are cyclin dependent protein kinases that are components of TFIIH, a complex that is involved in nucleotide excision repair and transcription initiation. Also known as MAT1 (menage a trois 1). 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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 31543889    18 CPLC-GKPMREP---VQVSTCGHRFCDTCLQEFLSEGVFKCPEDQLPLDYAK----IYPDPELEVQV 76
Cdd:TIGR00570   6 CPRCkTTKYRNPslkLMVNVCGHTLCESCVDLLFVRGSGSCPECDTPLRKNNfrvqLFEDPTVEKEV 72

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 31543889 308 GVLIWKIGSYGRRLQEAKAKPNLECFSPAFYTHKYGYKLQVSAFLNGNGSGEGTHLSIYIRVLPGAFDNLLEWPFARRVT 387
Cdd:cd03781   1 GTLLWKITDYSRKLQEAKGRDNLELFSPPFYTHRYGYKLQVSAFLNGNGSGEGSHLSVYIRVLPGEYDNLLEWPFSHRIT 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 31543889 388 FSLLDQSDPGLAKPQHVTETFHPDPNWKNFQKPGTWRgsLDESSLGFGYPKFISHQDIRKRNYVRDDAVFIRASVE 463
Cdd:cd03781  81 FTLLDQSDPSLSKPQHITETFTPDPTWKNFQKPSASR--LDESTLGFGYPKFISHEDLKKRNYIKDDAIFLRASVE 154

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 31543889 308 GVLIWKIGSYGRRLQEAKAKPNLECFSPAFYTHKYGYKLQVSAFLNGNGSGEGTHLSIYIRVLPGAFDNLLEWPFARRVT 387
Cdd:cd03780   1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 31543889 388 FSLLDQSdpglAKPQHVTETFHPDPNWKNFQKPGtwrgslDESSLGFGYPKFISHQDIR--KRNYVRDDAVFIRASVE 463
Cdd:cd03780  81 LMLLDQS----GKKNHIMETFKADPNSSSFKRPD------GEMNIASGCPRFVAHSVLEnaKNTYIKDDTLFLKVAVD 148

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 31543889 294 ELRRELEElSIGSDGVLIWKIGSYGRRLQEAKAKPNLECFSPAFYTHKYGYKLQVSAFLNGNGSGEGTHLSIYIRVLPGA 373
Cdd:cd03777  26 DLRFQVLE-TASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGE 104

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31543889 374 FDNLLEWPFARRVTFSLLDQsDPGlakPQHVTETFHPDPNWKNFQKPGTwrgsldESSLGFGYPKFISHQDIRKRNYVRD 453
Cdd:cd03777 105 YDALLPWPFKQKVTLMLMDQ-GSS---RRHLGDAFKPDPNSSSFKKPTG------EMNIASGCPVFVAQTVLENGTYIKD 174

                       170
                ....*....|
gi 31543889 454 DAVFIRASVE 463
Cdd:cd03777 175 DTIFIKVIVD 184

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 31543889 308 GVLIWKIGSYGRRLQEAKAKPNLECFSPAFYTHKYGYKLQVSAFLNGNGSGEGTHLSIYIRVLPGAFDNLLEWPFARRVT 387
Cdd:cd03776   1 GIYVWKIKNFSNLRRSMEAGSPVVIHSPGFYTSPPGYKLCARLNLSLPEARCPNYISLFVHLMQGENDSHLDWPFQGTIT 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 31543889 388 FSLLDQSDPGlakpQHVTETFHPDPNWKNFQKPGTWRgsldeSSLGFGYPKFISHQDIRKRNYVRDDAVFIRASV 462
Cdd:cd03776  81 LTLLDQSEPR----QNIHETMMSKPELLAFQRPTTDR-----NPKGFGYVEFAHIEDLLQRGFVKNDTLLIKIEV 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 31543889 308 GVLIWKIGSYGRRLQEAkakpnleCFSPAFYThkYGYKLQVSAFLNGNGSGeGTHLSIYIRVLPGAFDnLLEWPFARRVT 387
Cdd:cd00121   1 GKHTWKIVNFSELEGES-------IYSPPFEV--GGYKWRIRIYPNGDGES-GDYLSLYLELDKGESD-LEKWSVRAEFT 69

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 31543889 388 FSLLDQSDPglakpQHVTETFHPdpnWKNFQKPGTWrgsldesslgfGYPKFISHQDIRKRNYVRDDAVFIRASVE 463
Cdd:cd00121  70 LKLVNQNGG-----KSLSKSFTH---VFFSEKGSGW-----------GFPKFISWDDLEDSYYLVDDSLTIEVEVK 126

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 31543889 311 IWKIGSYGRRLQeaKAKPNLECFSPAFYTHKyGYKLQVSAFLNGNGSgEGTHLSIYIRVLPGAFDNLLEWPFARR-VTFS 389
Cdd:cd03771   5 VWRVRNFSQLLE--TTPKGTKIYSPRFYSPE-GYAFQVGLYPNGTES-YPGYTGLYFHLCSGENDDVLEWPCPNRqATMT 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31543889 390 LLDQsDPGLAKPQHVTETFHPDPN----------WKNFQKPGTWRGSLDES----SLGFGYPKFISHQDIRKRNYVRDDA 455
Cdd:cd03771  81 LLDQ-DPDIQQRMSNQRSFTTDPSmtssdngeyfWDRPSKVGSYDTDTNGCtcyrGPGYGWSTFISHSRLRRRDFLKGDD 159

                ....*...
gi 31543889 456 VFIRASVE 463
Cdd:cd03771 160 LIILLDFE 167

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 31543889   102 HLNTCSFNVVPCPNRCPAK-LSRRDLPAHLQHDCPKRRLKCEF----CGCDFSGEAYESH 156
Cdd:pfam02176   1 HLETCPFFPIPCPNGCCKKkILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

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
                ....*....|....*....|....*....|....*....|....*....|....*
gi 31543889  15 RLLCPLCGKPMREPVQvSTCGHRFCDTCLQEFLSEGVFKCPEDQLPLDYAKIYPD 69
Cdd:cd16643   1 KYECPICLMALREPVQ-TPCGHRFCKACILKSIREAGHKCPVDNEPLLENQLFPD 54

Uncharacterized conserved protein, contains RING Zn-finger [General function prediction only];

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 31543889  12 PKRRLLCPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCPE--------DQLPLDYakiypDPELEVQ 75
Cdd:COG5222 271 PNISLKCPLCHCLLRNPMKTPCCGHTFCDECIGTALLDSDFKCPNcsrkdvllDGLTPDI-----DKKLEVE 337

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
                ....*....|....*....|....*....|....*....|
gi 31543889  16 LLCPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCP 55
Cdd:cd16620   4 LKCPICKDLMKDAVLTPCCGNSFCDECIRTALLEEDFTCP 43

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 31543889  16 LLCPLCGKPMREPVqVSTCGHRFCDTCLQEFLSEGVFKCPED 57
Cdd:cd16449   1 LECPICLERLKDPV-LLPCGHVFCRECIRRLLESGSIKCPIC 41

RING finger, HC subclass, found in RING finger protein 138 (RNF138) and similar proteins; RNF138, also known as Nemo-like kinase-associated RING finger protein (NARF) or NLK-associated RING finger protein, is an E3 ubiquitin-protein ligase that plays an important role in glioma cell proliferation, apoptosis, and cell cycle. It specifically cooperates with the E2 conjugating enzyme E2-25K (Hip-2/UbcH1), regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF), and further suppresses Wnt-beta-catenin signaling. RNF138, together with three closely related proteins: RNF114, RNF125 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).

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 31543889  16 LLCPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCP 55
Cdd:cd16544   3 LTCPVCQEVLKDPVELPPCRHIFCKACILLALRSSGARCP 42

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 31543889    18 CPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCPE 56
Cdd:pfam00097   1 CPICLEEPKDPVTLLPCGHLFCSKCIRSWLESGNVTCPL 39

Modified RING finger, HC subclass (C3HC3D-type), found in neuregulin receptor degradation protein-1 (Nrdp1) and similar proteins; Nrdp1 (referred to as FLRF in mice), also known as RING finger protein 41 (RNF41), is an E3 ubiquitin-protein ligase that plays a critical role in the regulation of cell growth and apoptosis, inflammation and production of reactive oxygen species (ROS), as well as in doxorubicin (DOX)-induced cardiac injury. It promotes the degradation of the epidermal growth factor receptor (EGFR/ErbB) family member, ErbB3, which is independent of growth factor stimulation. It also promotes M2 macrophage polarization by ubiquitinating and activating transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) via Lys-63-linked ubiquitination. Moreover, Nrdp1 interacts with and modulates the activity of Parkin, a causative protein for early onset recessive juvenile parkinsonism (AR-JP). It also interacts with ubiquitin-specific protease 8 (USP8), which is involved in trafficking of various transmembrane proteins. Furthermore, Nrdp1 inhibits basal lysosomal degradation and enhances ectodomain shedding of JAK2-associated cytokine receptors. Its phosphorylation by the kinase Par-1b (also known as MARK2) is required for epithelial cell polarity. Nrdp1 contains an N-terminal modified C3HC3D-type RING-HC finger required for enhancing ErbB3 degradation, a B-box, a coiled-coil domain responsible for Nrdp1 oligomerization, and a C-terminal ErbB3-binding domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 31543889  16 LLCPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVfKCPEDQ 58
Cdd:cd16634   2 LICPICSGVLEEPLQAPHCEHAFCNACITEWLSRQQ-TCPVDR 43

RING finger, HC subclass, found in tripartite motif-containing protein 40 (TRIM40) and similar proteins; TRIM40, also known as probable E3 NEDD8-protein ligase or RING finger protein 35 (RNF35), is highly expressed in the gastrointestinal tract including the stomach, small intestine, and large intestine. It enhances neddylation of inhibitor of nuclear factor kappaB kinase subunit gamma (IKKgamma), inhibits the activity of nuclear factor-kappaB (NF-kappaB)-mediated transcription, and thus prevents inflammation-associated carcinogenesis in the gastrointestinal tract. TRIM40 belongs to the C-V subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domain, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as an uncharacterized region positioned C-terminal to the RBCC domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 31543889  17 LCPLCGKPMREPVQvSTCGHRFCDTCL----QEFLSEGVFKCP 55
Cdd:cd16583   7 VCPICQEPLKEAVS-TDCGHLFCRMCLtqhaKKASASGVFSCP 48

RING finger, HC subclass, found in tripartite motif-containing protein 39 (TRIM39) and similar proteins; TRIM39, also known as RING finger protein 23 (RNF23) or testis-abundant finger protein, is an E3 ubiquitin-protein ligase that plays a role in controlling DNA damage-induced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others. TRIM39 also functions as a regulator of several key processes in the proliferative cycle. It directly regulates p53 stability. It modulates cell cycle progression and DNA damage responses via stabilizing p21. Moreover, TRIM39 negatively regulates the nuclear factor kappaB (NFkappaB)-mediated signaling pathway through stabilization of Cactin, an inhibitor of NFkappaB- and Toll-like receptor (TLR)-mediated transcription, which is induced by inflammatory stimulants such as tumor necrosis factor alpha. Furthermore, TRIM39 is a MOAP-1-binding protein that can promote apoptosis signaling through stabilization of MOAP-1 via the inhibition of its poly-ubiquitination process. TRIM39 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 31543889  16 LLCPLCGKPMREPVQVsTCGHRFCDTCLQEFLSE--GVFKCPE 56
Cdd:cd16601   2 ASCSLCKEYLKDPVII-ECGHNFCRACITRFWEEldGDFPCPQ 43

RING finger, HC subclass, found in breast cancer type 1 susceptibility protein (BRCA1) and similar proteins; BRCA1, also known as RING finger protein 53 (RNF53), is a RING finger protein encoded by the tumor suppressor gene BRCA1 that regulates all DNA double-strand break (DSB) repair pathways. BRCA1 is frequently mutated in patients with hereditary breast and ovarian cancer (HBOC). Its mutation is also associated with an increased risk of pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. It plays an important role in the DNA damage response signaling and has been implicated in various cellular processes such as cell cycle regulation, transcriptional regulation, chromatin remodeling, DNA DSBs, and apoptosis. BRCA1 contains an N-terminal C3HC4-type RING-HC finger, and two BRCT (BRCA1 C-terminus domain) repeats at the C-terminus.

                        10        20        30
                ....*....|....*....|....*....|....
gi 31543889  16 LLCPLCGKPMREPVqvST-CGHRFCDTCLQEFLS 48
Cdd:cd16498  17 LECPICLELLKEPV--STkCDHQFCRFCILKLLQ 48

RING finger, HC subclass, found in really interesting new gene proteins RING1, RING2 and similar proteins; RING1, also known as polycomb complex protein RING1, RING finger protein 1 (RNF1), or RING finger protein 1A (RING1A), is a transcriptional repressor that is associated with the Polycomb group (PcG) protein complex involved in stable repression of gene activity. RING2, also known as huntingtin-interacting protein 2-interacting protein 3, HIP2-interacting protein 3, protein DinG, RING finger protein 1B (RING1B), RING finger protein 2 (RNF2), or RING finger protein BAP-1, is an E3 ubiquitin-protein ligase that interacts with both nucleosomal DNA and an acidic patch on histone H4 to achieve the specific monoubiquitination of K119 on histone H2A (H2AK119ub), thereby playing a central role in histone code and gene regulation. Both RING1 and RING2 are core components of polycomb repressive complex 1 (PRC1) that functions as an E3-ubuiquitin ligase transferring the mono-ubuiquitin mark to the C-terminal tail of Histone H2A at K118/K119. PRC1 is also capable of chromatin compaction, a function not requiring histone tails, and this activity appears important in gene silencing. RING2 acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity. Members of this family contain a C3HC4-type RING-HC finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 31543889  16 LLCPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCP 55
Cdd:cd16531   2 LMCPICLGIIKNTMTVKECLHRFCAECIEKALRLGNKECP 41

RING finger, HC subclass, found in tripartite motif-containing protein TRIM4 and similar proteins; TRIM4 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, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM4, also known as RING finger protein 87 (RNF87), is a cytoplasmic E3 ubiquitin-protein ligase that has recently evolved and is present only in higher mammals. It transiently interacts with mitochondria, induces mitochondrial aggregation and sensitizes the cells to hydrogen peroxide (H2O2) induced death. Its interaction with peroxiredoxin 1 (PRX1) is critical for the regulation of H2O2 induced cell death. Moreover, TRIM4 functions as a positive regulator of RIG-I-mediated type I interferon induction. It regulates the K63-linked ubiquitination of RIG-1 and assembly of antiviral signaling complex at the mitochondria.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 31543889  10 EKPKRRLLCPLCGKPMREPVQVStCGHRFCDTCLQEFLSE--GVFKCPEDQLPLDYAKIYPD 69
Cdd:cd16590   1 EDIQEELTCPICLDYFQDPVSIE-CGHNFCRGCLHRNWAPggGPFPCPECRHPSAPAALRPN 61

Modified RING finger domain; Modified RING finger domain, without the full complement of Zn2+-binding ligands. Probable involvement in E2-dependent ubiquitination.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 31543889     16 LLCPLCGKPMREPVqVSTCGHRFCDTCLQEFLSEgVFKCPEDQLPLDYAKIYPDPEL 72
Cdd:smart00504   2 FLCPISLEVMKDPV-ILPSGQTYERSAIEKWLLS-HGTDPVTGQPLTHEDLIPNLAL 56

Modified RING finger, HC subclass (C3HC3D-type), found in Caenorhabditis elegans putative GTP-binding protein trim-23 homolog (arc-1) and similar proteins; arc-1, also called RING-type E3 ubiquitin transferase arc-1, is an E3 ubiquitin-protein ligase that mediates E2-dependent protein ubiquitination. arc-1 contains a modified C3HC3D-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 31543889  15 RLLCPLCGK------PMREPVQVSTCGHRFCDTCLQEFL--SEGVFKCPEDQLPL 61
Cdd:cd23124   1 ELECGICQQeysaddPLLIPRILTECGHTICTNCAGTILgqSSGSIFCPFDRIVT 55

RING-type zinc-finger; This zinc-finger is a typical RING-type of plant ubiquitin ligases.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 31543889    18 CPLCGKPMREPVqvSTCGHRFCDTCLQEFL--SEGVFKCP 55
Cdd:pfam13445   1 CPICLELFTDPV--LPCGHTFCRECLEEMSqkKGGKFKCP 38

RING finger, HC subclass, found in RING finger protein 166 (RNF166) and similar proteins; RNF166 is encoded by the gene RNF166 targeted by thyroid hormone receptor alpha1 (TRalpha1), which is important in brain development. It plays an important role in RNA virus-induced interferon-beta production by enhancing the ubiquitination of TRAF3 and TRAF6. RNF166, together with three closely related proteins: RNF114, RNF125 and RNF138, 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).

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 31543889  16 LLCPLCGKPMREPVQVSTCGHRFCDTCLQEFLSEGVFKCPEDQLP 60
Cdd:cd16549   2 FSCPICLEVYHKPVVITSCGHTFCGECLQPCLQVASPLCPLCRMP 46

RING finger, HC subclass, found in tripartite motif-containing protein 8 (TRIM8) and similar proteins; TRIM8, also known as glioblastoma-expressed RING finger protein (GERP) or RING finger protein 27 (RNF27), is a probable E3 ubiquitin-protein ligase that may promote proteasomal degradation of suppressor of cytokine signaling 1 (SOCS1) and further regulate interferon-gamma signaling. It functions as a new p53 modulator that stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation. TRIM8 deficit dramatically impairs p53 stabilization and activation in response to chemotherapeutic drugs. TRIM8 also modulates tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta)-triggered nuclear factor-kappaB (NF- kappa B) activation by targeting transforming growth factor beta (TGFbeta) activated kinase 1 (TAK1) for K63-linked polyubiquitination. Moreover, TRIM8 modulates translocation of phosphorylated STAT3 into the nucleus through interaction with Hsp90beta and consequently regulates transcription of Nanog in embryonic stem cells. It also interacts with protein inhibitor of activated STAT3 (PIAS3), which inhibits IL-6-dependent activation of STAT3. TRIM8 belongs to the C-V 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 domain, as well as an uncharacterized region positioned C-terminal to the RBCC domain. The coiled coil domain is required for homodimerization and the region immediately C-terminal to the RING motif is sufficient to mediate the interaction with SOCS1.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 31543889  16 LLCPLCGKPMREPVQVStCGHRFCDTCLQEFLSE--GVFKCPE 56
Cdd:cd16580  12 LICPICLHVFVEPVQLP-CKHNFCRGCIGEAWAKdaGLVRCPE 53

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 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 31543889  16 LLCPLCGKPMREPVqVSTCGHRFCDTCLQEFL---SEGVFKCPE 56
Cdd:cd16609   4 LTCSICLGLYQDPV-TLPCQHSFCRACIEDHWrqkDEGSFSCPE 46

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
                ....*....|....*....|....*....|.
gi 31543889  13 KRRLLCPLCGKPMREPVQVStCGHRFCDTCL 43
Cdd:cd16599   2 KEELLCPICYEPFREAVTLR-CGHNFCKGCV 31

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        30        40
                ....*....|....*....|....*....|....*....|
gi 31543889  17 LCPLCGKPMREPVQVStCGHRFCDTCLQEFLSEGVFKCPE 56
Cdd:cd16639   3 LCSDCRNILRRPFQAQ-CGHRYCSYCLKKILSSGPQKCAA 41