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 817250525 417 GEYVWRLKDFPGTLAELREKPTRVIHSPGFYTSPFGYKFCLRLNL-TRGSGKGErggeeWLSLFIHGMQGENDDFLDWPF 495
Cdd:cd00270    1 GVLIWKIKDYSRKLQEAVAGSNTVLYSPPFYTSRYGYKLCLRLYLnGDGTGKGT-----HLSLFVHVMKGEYDALLEWPF 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 817250525 496 SGIITFSLLDCGAGRPKAHITETLHSSPDRQSFSRPQMHRNPKGFGYTEFAPLSKVVEGSgraeYVHEGTLHIRATV 572
Cdd:cd00270   76 RGKITLTLLDQSDDSKRKHITETFMPDPNSSAFQRPPTGENNIGFGYPEFVPLEKLESRG----YVKDDTLFIKVEV 148

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817250525  32 LDPKYECPICLLALRAPLQTACGHRFCKDCIYNSLSESSrRCPIDNTPLKETDLfPDSCAEREVLQlrvrcPNTSLGcSQ 111
Cdd:COG5432   22 LDSMLRCRICDCRISIPCETTCGHTFCSLCIRRHLGTQP-FCPVCREDPCESRL-RGSSGSREINE-----SHARNR-DL 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817250525 112 VLDLMYIEHHTQACSFQPVLCPNEC-----SATV----------------LQKELDHHLESQCLLRLKLCALCDLPYPFN 170
Cdd:COG5432   94 LRKVLESLCRLPRPIKEERPCRWETviaqdSASGdeeweddlasnsspasIAKKTSRDSKKRKREDLVHCPACSNLVPHN 173

                 ....*....
gi 817250525 171 EEQLHLATC 179
Cdd:COG5432  174 QINQHLDSC 182

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 817250525 417 GEYVWRLKDFPGTLAELREKPTRVIHSPGFYTSPFGYKFCLRLNL-TRGSGKGErggeeWLSLFIHGMQGENDDFLDWPF 495
Cdd:cd00270    1 GVLIWKIKDYSRKLQEAVAGSNTVLYSPPFYTSRYGYKLCLRLYLnGDGTGKGT-----HLSLFVHVMKGEYDALLEWPF 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 817250525 496 SGIITFSLLDCGAGRPKAHITETLHSSPDRQSFSRPQMHRNPKGFGYTEFAPLSKVVEGSgraeYVHEGTLHIRATV 572
Cdd:cd00270   76 RGKITLTLLDQSDDSKRKHITETFMPDPNSSAFQRPPTGENNIGFGYPEFVPLEKLESRG----YVKDDTLFIKVEV 148

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 817250525    38 CPICL-LALRAPLQTACGHRFCKDCIYNSLSESSRRCPI 75
Cdd:smart00184   1 CPICLeEYLKDPVILPCGHTFCRSCIRKWLESGNNTCPI 39

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 817250525   37 ECPICLLALRAPLQ-TACGHRFCKDCIYNSLsESSRRCPI 75
Cdd:pfam13923   1 MCPICMDMLKDPSTtTPCGHVFCQDCILRAL-RAGNECPL 39

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 817250525   32 LDPKYECPICLLALRAPLQTACGHRFCKDCIYNSLSESSrRCPIDNTPLKETDL 85
Cdd:TIGR00599  23 LDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQP-KCPLCRAEDQESKL 75

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817250525   434 REKPTRVIHSPGFYTspFGYKFCLRLNLTRGSgkgerggeewLSLFIHGMQGENDDfLDWPFSGIITFSLLdcgagrpka 513
Cdd:smart00061  11 RLEEGESYFSPSEEH--FNIPWRLKIYRKNGF----------LSLYLHCEKEECDS-RKWSIEAEFTLKLV--------- 68

                           90       100       110
                   ....*....|....*....|....*....|....
gi 817250525   514 hitetlhsSPDRQSFSRPQMHR--NPKGFGYTEF 545
Cdd:smart00061  69 --------SQNGKSLSKKDKHVfeKPSGWGFSKF 94

E3 ubiquitin-protein ligase RMA2; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 817250525  36 YECPICLLALRAPLQTACGHRFCKDCI--YNSLSESSR-------------RCPIDNTPLKETDLFP 87
Cdd:PLN03208  19 FDCNICLDQVRDPVVTLCGHLFCWPCIhkWTYASNNSRqrvdqydhkreppKCPVCKSDVSEATLVP 85

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 817250525 417 GEYVWRLKDFPGTLAELREKPTRVIHSPGFYTSPFGYKFCLRLNL-TRGSGKGErggeeWLSLFIHGMQGENDDFLDWPF 495
Cdd:cd00270    1 GVLIWKIKDYSRKLQEAVAGSNTVLYSPPFYTSRYGYKLCLRLYLnGDGTGKGT-----HLSLFVHVMKGEYDALLEWPF 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 817250525 496 SGIITFSLLDCGAGRPKAHITETLHSSPDRQSFSRPQMHRNPKGFGYTEFAPLSKVVEGSgraeYVHEGTLHIRATV 572
Cdd:cd00270   76 RGKITLTLLDQSDDSKRKHITETFMPDPNSSAFQRPPTGENNIGFGYPEFVPLEKLESRG----YVKDDTLFIKVEV 148

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 817250525  35 KYECPICLLALRAPLQTACGHRFCKDCIYNSLSESSRRCPIDNTPLKETDLFPDSCAE 92
Cdd:cd16643    1 KYECPICLMALREPVQTPCGHRFCKACILKSIREAGHKCPVDNEPLLENQLFPDNFAK 58

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 817250525 417 GEYVWRLKDFPGTLAELREKPTRVIHSPGFYTSPFGYKFCLRLNLTrGSGKGeRGGEewLSLFIHGMQGENDDFLDWPFS 496
Cdd:cd03778   19 GVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLN-GDGTG-RGTH--LSLFFVVMKGPNDALLRWPFN 94

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 817250525 497 GIITFSLLDcgaGRPKAHITETLHSSPDRQSFSRPQMHRNPKGfGYTEFAPLSKvveGSGRAEYVHEGTLHIRATV 572
Cdd:cd03778   95 QKVTLMLLD---QNNREHVIDAFRPDVTSSSFQRPVNDMNIAS-GCPLFCPVSK---*EAKNSYVRDDAIFIKAIV 163

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 817250525 417 GEYVWRLKDFPGTLAELREKPTRVIHSPGFYTSPFGYKFCLRLNLT-RGSGKGERggeewLSLFIHGMQGENDDFLDWPF 495
Cdd:cd03780    1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNgDGSGKGTH-----LSLYFVVMRGEFDSLLQWPF 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 817250525 496 SGIITFSLLDCGAGrpKAHITETLHSSPDRQSFSRPQMHRNPKGfGYTEFAPLSkVVEGSGRAeYVHEGTLHIRATV 572
Cdd:cd03780   76 RQRVTLMLLDQSGK--KNHIMETFKADPNSSSFKRPDGEMNIAS-GCPRFVAHS-VLENAKNT-YIKDDTLFLKVAV 147

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 817250525 417 GEYVWRLKDFpgtlaelREKPTRVIHSPGFYTspFGYKFCLRLNLtrgsgKGERGGEEWLSLFIHGMQGENDDfLDWPFS 496
Cdd:cd00121    1 GKHTWKIVNF-------SELEGESIYSPPFEV--GGYKWRIRIYP-----NGDGESGDYLSLYLELDKGESDL-EKWSVR 65

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 817250525 497 GIITFSLLDCGAGRPKAHITETLHSSpdrqsfsrpqmhRNPKGFGYTEFAPLSKVVEgsgrAEYVHEGTLHIRATVR 573
Cdd:cd00121   66 AEFTLKLVNQNGGKSLSKSFTHVFFS------------EKGSGWGFPKFISWDDLED----SYYLVDDSLTIEVEVK 126

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        40
                 ....*....|....*....|....*....|....*....|....*.
gi 817250525  37 ECPICLLALRAPLQTACGHRFCKDCIYNSLSESSR--RCPIDNTPL 80
Cdd:cd16498   18 ECPICLELLKEPVSTKCDHQFCRFCILKLLQKKKKpaPCPLCKKSV 63

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 817250525  32 LDPKYECPICLLALRAPLQ-TACGHRFCKDCIyNSLSESSRRCPIDNTPLK 81
Cdd:cd23126    1 LDKKYECPVCCQVLRYPVQfEECGHRVCSSCL-PELLRVEPRCPIDQGPID 50

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 817250525  36 YECPICLLALRAPLQTACGHRFCKDCIYNSLSESSRRCPID 76
Cdd:cd16449    1 LECPICLERLKDPVLLPCGHVFCRECIRRLLESGSIKCPIC 41

RING finger, HC subclass, found in RING finger protein 10 (RNF10) and similar proteins; RNF10 is an E3 ubiquitin-protein ligase that interacts with mesenchyme Homeobox 2 (MEOX2) transcription factor, a regulator of the proliferation, differentiation and migration of vascular smooth muscle cells and cardiomyocytes; it enhances Meox2 activation of the p21 promoter. It also regulates the expression of myelin-associated glycoprotein (MAG) genes and is required for myelin production in Schwann cells of the peripheral nervous system. Moreover, RNF10 regulates retinoic acid-induced neuronal differentiation and the cell cycle exit of P19 embryonic carcinoma cells. RNF10 contains a C3HC4-type RING-HC finger and three putative nuclear localization signals.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 817250525  36 YECPICLLALRAPLQTACGHRFCKDCI--YNSLSES-SRRCPIDNTPLKETDL 85
Cdd:cd16536    1 PQCPICLEPPVAPRITRCGHIFCWPCIlrYLSLSEKkWRKCPICFESIHKKDL 53

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 817250525 418 EYVWRLKDFPGTLAElrEKPTRVIHSPGFYtSPFGYKFCLRLNLtrgSGKGERGGEewLSLFIHGMQGENDDFLDWP 494
Cdd:cd03782    3 EHIWHIRNFTQLLAT--TPPNGKIYSPPFL-SSTGYSFQVGLYL---NGTDDYPGN--LAIYLHLTSGPNDDQLQWP 71

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) and similar proteins; TRAF4, also known as cysteine-rich domain associated with RING and Traf domains protein 1, metastatic lymph node gene 62 protein (MLN 62), or RING finger protein 83 (RNF83), is a member of the 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 nervous system, as well as in carcinogenesis. TRAF4 promotes the growth and invasion of colon cancer through the Wnt/beta-catenin pathway. It contributes to the TNFalpha-induced activation of the 70 kDa ribosomal protein S6 kinase (p70s6k) signaling pathway, and activation of transforming growth factor beta (TGF-beta)-induced SMAD-dependent signaling and non-SMAD signaling in breast cancer. It also enhances osteosarcoma cell proliferation and invasion by the Akt signaling pathway. Moreover, TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration. TRAF4 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
                 ....*....|....*....|....*....|....*....|...
gi 817250525  35 KYECPICLLALRAPLQ-TACGHRFCKDCIYNSLSESSRRCPID 76
Cdd:cd16641    1 RLLCPLCRLPMREPVQiSTCGHRFCDTCLQEFLSEGVFKCPED 43

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 817250525  33 DPKYECPICLLALRAPLQTAC-GHRFCKDCIYNSLSESSRRCPIDNTPLKETDL 85
Cdd:cd16620    1 PDELKCPICKDLMKDAVLTPCcGNSFCDECIRTALLEEDFTCPTCKEPDVSPDA 54

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 817250525 420 VWRLKDFPGTLaelrEKPTR--VIHSPGFYtSPFGYKFCLRL----NLTRGSGKgerggeeWLSLFIHGMQGENDDFLDW 493
Cdd:cd03783    5 VWRVRNFSQIL----ENTTKgdVLQSPRFY-SPEGYGYGVSLyplsNESDYSGN-------YTGLYFHLCSGENDAVLEW 72

                 .
gi 817250525 494 P 494
Cdd:cd03783   73 P 73

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 817250525  36 YECPICLLALRAPLQTACGHRFCKDCIYNSLSESSRRCPIDNTPL 80
Cdd:cd16542    2 FDCAVCLEVLHQPVRTRCGHVFCRPCIATSLRNNTWTCPYCRAYL 46

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 817250525   37 ECPICLLALRAPLQ-TACGHRFCKDCIYNSLsESSRRCPI 75
Cdd:pfam13923   1 MCPICMDMLKDPSTtTPCGHVFCQDCILRAL-RAGNECPL 39

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817250525  32 LDPKYECPICLLALRAPLQTACGHRFCKDCIYNSLSESSrRCPIDNTPLKETDLfPDSCAEREVLQlrvrcPNTSLGcSQ 111
Cdd:COG5432   22 LDSMLRCRICDCRISIPCETTCGHTFCSLCIRRHLGTQP-FCPVCREDPCESRL-RGSSGSREINE-----SHARNR-DL 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817250525 112 VLDLMYIEHHTQACSFQPVLCPNEC-----SATV----------------LQKELDHHLESQCLLRLKLCALCDLPYPFN 170
Cdd:COG5432   94 LRKVLESLCRLPRPIKEERPCRWETviaqdSASGdeeweddlasnsspasIAKKTSRDSKKRKREDLVHCPACSNLVPHN 173

                 ....*....
gi 817250525 171 EEQLHLATC 179
Cdd:COG5432  174 QINQHLDSC 182

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 817250525  37 ECPICLLALRAPLQTACGHRFCKDCIYNSLSESSrRCPIDNTPLKETDL 85
Cdd:cd23148    5 RCHICKDLLKAPMRTPCNHTFCSFCIRTHLNNDA-RCPLCKAEVTESGL 52

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM5, TRIM6, TRIM22, TRIM34 and similar proteins; TRIM5, TRIM6, TRIM22, and TRIM34, four closely related tripartite motif-containing proteins, belong 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. TRIM5, also known as RING finger protein 88 (RNF88), is a capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. Its retroviral restriction activity correlates with the ability to activate TAK1-dependent innate immune signaling. TRIM5 also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Moreover, TRIM5 plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2. It also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction. TRIM6, also known as RING finger protein 89 (RNF89), is an E3-ubiquitin ligase that cooperates with the E2-ubiquitin conjugase UbE2K to catalyze the synthesis of unanchored K48-linked polyubiquitin chains, and further stimulates the interferon-I kappa B kinase epsilon (IKKepsilon) kinase-mediated antiviral response. It also regulates the transcriptional activity of Myc during the maintenance of embryonic stem (ES) cell pluripotency, and may act as a novel regulator for Myc-mediated transcription in ES cells. TRIM22, also known as 50 kDa-stimulated trans-acting factor (Staf-50) or RING finger protein 94 (RNF94), is an E3 ubiquitin-protein ligase that plays an integral role in the host innate immune response to viruses. It has been shown to inhibit the replication of a number of viruses, including HIV-1, hepatitis B, and influenza A. TRIM22 acts as a suppressor of basal HIV-1 long terminal repeat (LTR)-driven transcription by preventing the transcription factor specificity protein 1 (Sp1) binding to the HIV-1 promoter. It also controls FoxO4 activity and cell survival by directing Toll-like receptor 3 (TLR3)-stimulated cells toward type I interferon (IFN) type I gene induction or apoptosis. Moreover, TRIM22 can activate the noncanonical nuclear factor-kappaB (NF-kappaB) pathway by activating I kappa B kinase alpha (IKKalpha). It also regulates nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-kappaB. TRIM34, also known as interferon-responsive finger protein 1 or RING finger protein 21 (RNF21), may function as antiviral protein that contribute to the defense against retroviral infections.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 817250525  38 CPICLLALRAPLQTACGHRFCKDCIY-----NSLSESSRRCPIDNTPLKETDLFPD 88
Cdd:cd16591    9 CPICLELLTEPLSLDCGHSFCQACITanhkeSVNQEGESSCPVCRTSYQPENLRPN 64

RING finger, HC subclass, found in RING finger protein 213 (RNF213) and similar proteins; RNF213, also known as ALK lymphoma oligomerization partner on chromosome 17 or Moyamoya steno-occlusive disease-associated AAA+ and RING finger protein (mysterin), is an intracellular soluble protein that functions as an E3 ubiquitin-protein ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell. It plays a unique role in endothelial cells for proper gene expression in response to inflammatory signals from the environment. Mutations in RNF213 may be associated with Moyamoya disease (MMD), an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. It also acts as a nuclear marker for acanthomorph phylogeny. RNF213 contains two tandem enzymatically active AAA+ ATPase modules and a C3HC4-type RING-HC finger. It can form a huge ring-shaped oligomeric complex.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 817250525  37 ECPICLLALRAPLQTACGHRFCKDCIYNSLsESSRRCPI 75
Cdd:cd16561    4 ECSICLEDLNDPVKLPCDHVFCEECIRQWL-PGQMSCPL 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        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 817250525   32 LDPKYECPICLLALRAPLQTACGHRFCKDCIYNSLSESSrRCPIDNTPLKETDL 85
Cdd:TIGR00599  23 LDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCLSNQP-KCPLCRAEDQESKL 75

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 817250525   38 CPICLLALRAPLQTA-CGHRFCKDCIYNSLSESSRRCPI 75
Cdd:pfam00097   1 CPICLEEPKDPVTLLpCGHLFCSKCIRSWLESGNVTCPL 39

Modified RING finger, H2 subclass (C3H2C2D-type), found in zinc finger SWIM domain-containing protein 2 (ZSWIM2) and similar proteins; ZSWIM2, also known as MEKK1-related protein X (MEX) or ZZ-type zinc finger-containing protein 2, is a testis-specific E3 ubiquitin ligase that promotes death receptor-induced apoptosis through Fas, death receptor (DR) 3 and DR4 signaling. ZSWIM2 is self-ubiquitinated and targeted for degradation through the proteasome pathway. It acts as an E3 ubiquitin ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c, or UbcH6. ZSWIM2 contains four putative zinc-binding domains including an N-terminal SWIM (SWI2/SNF2 and MuDR) domain critical for its ubiquitination, and two modified RING-H2 fingers separated by a ZZ zinc finger domain, which was required for interaction with UbcH5a and its self-association. This model corresponds to the second RING-H2 finger, which is not a canonical C3H2C3-type, but a modified C3H2C2D-type.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 817250525  37 ECPICLLALRAPLQT---ACGHRFCKDCIYNSLSESSRRCPIDNTP 79
Cdd:cd16486    1 QCRICLKAFQLGQHVrtlPCRHKFHRDCIDNWLLHSRNSCPIDGQV 46

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of 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 817250525  38 CPICLLALRAPLQTACGHRFCKDCI---YNSLSESSRRCP 74
Cdd:cd16597    8 CSICLELFKDPVTLPCGHNFCGVCIektWDSQHGSEYSCP 47

Modified RING finger, HC subclass (C3HC3D-type), found in ligand of numb protein X 2 (LNX2); LNX2, also known as numb-binding protein 2, or PDZ domain-containing RING finger protein 1 (PDZRN1), is a PDZ domain-containing RING-type E3 ubiquitin 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. It interacts with contactin-associated protein 4 (Caspr4, also known as CNTNAP4) in a PDZ domain-dependent manner, which modulates the proliferation and neuronal differentiation of neural progenitor cells (NPCs). LNX2 contains an N-terminal modified C3HC3D-type RING-HC finger, a NPAF motif for Numb/ Numblike-LNX interaction, and four PDZ domains necessary for the binding of substrates, including ErbB2, RhoC, the presynaptic protein CAST, the melanoma/cancer-testis antigen MAGEB18 and several proteins associated with cell junctions, such as JAM4 and the Coxsackievirus and adenovirus receptor (CAR).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 817250525  33 DPKYECPICLLALRAPLQTACGHRFCKDCIYNSLSESSrRCPID 76
Cdd:cd16780    1 DDDLVCHICLQPLLQPLDTPCGHTFCFKCLRNFLQEKD-FCPLD 43

RING finger, HC subclass, found in RING finger protein 146 (RNF146) and similar proteins; RNF146, also known as dactylidin, or iduna, is a cytoplasmic E3 ubiquitin-protein ligase that is responsible for PARylation-dependent ubiquitination (PARdU). It displays neuroprotective property due to its inhibition of Parthanatos, a PAR dependent cell death, via binding with Poly(ADP-ribose) (PAR). It also modulates PAR polymerase-1 (PARP-1)-mediated oxidative cell injury in cardiac myocytes. Moreover, RNF146 mediates tankyrase-dependent degradation of axin, thereby positively regulating Wnt signaling. It also facilitates DNA repair and protects against cell death induced by DNA damaging agents or gamma-irradiation by translocating to the nucleus after cellular injury and promoting the ubiquitination and degradation of various nuclear proteins involved in DNA damage repair. Furthermore, RNF146 is implicated in neurodegenerative disease and cancer development. It regulates the development and progression of non-small cell lung cancer (NSCLC) by enhancing cell growth, invasion, and survival. RNF146 contains an N-terminal C3HC4-type RING-HC finger followed by a WWE domain with a poly(ADP-ribose) (PAR) binding motif at the tail.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 817250525  37 ECPICLLALRAPLQTACGHRFCKDCIyNSLSESSRRCPI 75
Cdd:cd16546    2 ECPICLQTCIHPVKLPCGHIFCYLCV-KGVAWQSKRCAL 39

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        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 817250525  38 CPICLLALRAPLQTACGHRFCKDCIYNSLSESSRR----CPIDNTPLKETDL 85
Cdd:cd16583    8 CPICQEPLKEAVSTDCGHLFCRMCLTQHAKKASASgvfsCPVCRKPCSEGVL 59

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 817250525  175 HLATCAQVMVSCE--LCGCVVARGELPTHRSDSCPRVVVGCPYTEHGCSHKTVRADLDAH 232
Cdd:pfam02176   1 HLETCPFFPIPCPngCCKKKILREDLPDHLELDCPKAEVPCPFKVFGCKEDVKREALQRH 60

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 817250525  38 CPICLLALRAPLQTACGHRFCKDCIYNSLSESS--RRCPIDNTPLKE 82
Cdd:cd16580   14 CPICLHVFVEPVQLPCKHNFCRGCIGEAWAKDAglVRCPECNQAYNQ 60

RING finger, HC subclass, found in tripartite motif-containing protein 72 (TRIM72) and similar proteins; TRIM72, also known as Mitsugumin-53 (MG53), is a muscle-specific protein that plays a central role in cell membrane repair by nucleating the assembly of the repair machinery at muscle injury sites. It is required in repair of alveolar epithelial cells under plasma membrane stress failure. It interacts with dysferlin to regulate sarcolemmal repair. Upregulation of TRIM72 develops obesity, systemic insulin resistance, dyslipidemia, and hyperglycemia, as well as induces diabetic cardiomyopathy through transcriptional activation of the peroxisome proliferation-activated receptor alpha (PPAR-alpha) signaling pathway. Compensation for the absence of AKT signaling by ERK signaling during TRIM72 overexpression leads to pathological hypertrophy. Moreover, TRIM72 functions as a novel negative feedback regulator of myogenesis by targeting insulin receptor substrate-1 (IRS-1). It is transcriptionally activated by the synergism of myogenin (MyoD) and myocyte enhancer factor 2 (MEF2). TRIM72 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
                 ....*....|....*....|....*
gi 817250525  38 CPICLLALRAPLQTACGHRFCKDCI 62
Cdd:cd16612    7 CPLCLKLFQSPVTTECGHTFCQDCL 31

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 817250525  26 YEFVPTLDpkYECPICLLALRAPLQTACGHRFCKDCIYNSL-SESSRRCPI 75
Cdd:COG5574  208 LPFIPLAD--YKCFLCLEEPEVPSCTPCGHLFCLSCLLISWtKKKYEFCPL 256

RING finger, HC subclass, found in postreplication repair protein RAD18 and similar proteins; RAD18, also known as HR18 or RING finger protein 73 (RNF73), is an E3 ubiquitin-protein ligase involved in post replication repair of UV-damaged DNA via its recruitment to stalled replication forks. It associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on K164. It also interacts with another E2 ubiquitin conjugating enzyme RAD6 to form a complex that monoubiquitinates proliferating cell nuclear antigen at stalled replication forks in DNA translesion synthesis. Moreover, Rad18 is a key factor in double-strand break DNA damage response (DDR) pathways via its association with K63-linked polyubiquitylated chromatin proteins. It can function as a mediator for DNA damage response signals to activate the G2/M checkpoint in order to maintain genome integrity and cell survival after ionizing radiation (IR) exposure. RAD18 contains a C3HC4-type RING-HC finger, a ubiquitin-binding zinc finger domain (UBZ), a SAP (SAF-A/B, Acinus and PIAS) domain, and a RAD6-binding domain (R6BD).

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 817250525  32 LDPKYECPICLLALR-APLQTACGHRFCKDCIYNSLSESSrRCPIDNTPLKETDL 85
Cdd:cd16529    1 LDDLLRCPICFEYFNtAMMITQCSHNYCSLCIRRFLSYKT-QCPTCRAAVTESDL 54

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 817250525   434 REKPTRVIHSPGFYTspFGYKFCLRLNLTRGSgkgerggeewLSLFIHGMQGENDDfLDWPFSGIITFSLLdcgagrpka 513
Cdd:smart00061  11 RLEEGESYFSPSEEH--FNIPWRLKIYRKNGF----------LSLYLHCEKEECDS-RKWSIEAEFTLKLV--------- 68

                           90       100       110
                   ....*....|....*....|....*....|....
gi 817250525   514 hitetlhsSPDRQSFSRPQMHR--NPKGFGYTEF 545
Cdd:smart00061  69 --------SQNGKSLSKKDKHVfeKPSGWGFSKF 94