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 568979512 377 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 456
Cdd:cd03777    1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 457 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 536
Cdd:cd03777   81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                        170       180
                 ....*....|....*....|....*.
gi 568979512 537 VAQTVLENGTYIKDDTIFIKVIVDTS 562
Cdd:cd03777  161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568979512  135 HLKNeCQFEELPCLRADCKEKVLRKDLRDHVEKACKYREATCSH----CKSQVPMIKLQKH 191
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 568979512  196 CPCVVVSCPHKCSVQTLLRSELSAHLSE-CVNAPSTCSFKRYGC--VFQGTNQQ 246
Cdd:pfam02176   5 CPFFPIPCPNGCCKKKILREDLPDHLELdCPKAEVPCPFKVFGCkeDVKREALQ 58

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 568979512 377 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 456
Cdd:cd03777    1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 457 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 536
Cdd:cd03777   81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                        170       180
                 ....*....|....*....|....*.
gi 568979512 537 VAQTVLENGTYIKDDTIFIKVIVDTS 562
Cdd:cd03777  161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568979512  135 HLKNeCQFEELPCLRADCKEKVLRKDLRDHVEKACKYREATCSH----CKSQVPMIKLQKH 191
Cdd:pfam02176   1 HLET-CPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

RIM-binding protein of the cytomatrix active zone; This is a family of proteins that form part of the CAZ (cytomatrix at the active zone) complex which is involved in determining the site of synaptic vesicle fusion. The C-terminus is a PDZ-binding motif that binds directly to RIM (a small G protein Rab-3A effector). The family also contains four coiled-coil domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  243 TNQQikaheaSSAVQHVNLLKEWSNSLEKKVSLLQNES--------------VEKNKSIQSLHNQICSFEIEIERQKEML 308
Cdd:pfam10174 316 TNQN------SDCKQHIEVLKESLTAKEQRAAILQTEVdalrlrleekesflNKKTKQLQDLTEEKSTLAGEIRDLKDML 389

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  309 RNNESKILHLQRVIDSQAEKLKELDKEIrpfrqnweeaDSMKSSVESLQ----NRVTELESVDKSAGQAARNTGLLESQL 384
Cdd:pfam10174 390 DVKERKINVLQKKIENLQEQLRDKDKQL----------AGLKERVKSLQtdssNTDTALTTLEEALSEKERIIERLKEQR 459

                  ....*
gi 568979512  385 SRHDQ 389
Cdd:pfam10174 460 EREDR 464

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 568979512  196 CPCVVVSCPHKCSVQTLLRSELSAHLSE-CVNAPSTCSFKRYGC--VFQGTNQQ 246
Cdd:pfam02176   5 CPFFPIPCPNGCCKKKILREDLPDHLELdCPKAEVPCPFKVFGCkeDVKREALQ 58

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  51 KCEKCRLVLCNPKQTECGHRFCESCMAALLsSSSPKCTACQESiIKDKVFKDNCCKREIlaLQVYCRNEGRgcaeqltlg 130
Cdd:COG5432   27 RCRICDCRISIPCETTCGHTFCSLCIRRHL-GTQPFCPVCRED-PCESRLRGSSGSREI--NESHARNRDL--------- 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 131 hLLVHLKNECQFEELPCLRADCKEKVLRKDLRDHVEKACKYREATCSH----CKSQVPMIKLQKHED-TDCPCVVVSCPH 205
Cdd:COG5432   94 -LRKVLESLCRLPRPIKEERPCRWETVIAQDSASGDEEWEDDLASNSSpasiAKKTSRDSKKRKREDlVHCPACSNLVPH 172

                        170       180
                 ....*....|....*....|....*
gi 568979512 206 KcsvqtllrsELSAHLSECVNAPST 230
Cdd:COG5432  173 N---------QINQHLDSCLNSPSS 188

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        40
                  ....*....|....*....|....*....|....*....|
gi 568979512   55 CRLVLCNPKQ----TECGHRFCESCMAALLSSSSPKCTAC 90
Cdd:pfam00097   1 CPICLEEPKDpvtlLPCGHLFCSKCIRSWLESGNVTCPLC 40

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 568979512   43 VKTVEDKYKCEKCRLVLCNPKQTECGHRFCESCMAALLsSSSPKCTAC----QESIIK 96
Cdd:TIGR00599  20 LYPLDTSLRCHICKDFFDVPVLTSCSHTFCSLCIRRCL-SNQPKCPLCraedQESKLR 76

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 568979512 377 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 456
Cdd:cd03777    1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 457 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 536
Cdd:cd03777   81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                        170       180
                 ....*....|....*....|....*.
gi 568979512 537 VAQTVLENGTYIKDDTIFIKVIVDTS 562
Cdd:cd03777  161 VAQTVLENGTYIKDDTIFIKVIVDTS 186

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 568979512 415 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 494
Cdd:cd03780    1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 568979512 495 LMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVFVAQTVLENG--TYIKDDTIFIKVIVD 560
Cdd:cd03780   81 LMLLDQSGKKNHIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLENAknTYIKDDTLFLKVAVD 148

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF1 subfamily, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF1 expression is the most restricted among the TRAFs. It is found exclusively in activated lymphocytes, dendritic cells and certain epithelia. TRAF1 associates, directly or indirectly through heterodimerization with TRAF2, with the TNFR family receptors TNFR-2, CD30, RANK, CD40 and LMP1, among others. It also binds the intracellular proteins TRADD, TANK, TRIP, RIP1, RIP2 and FLIP. TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events. TRAF1 contains one zinc finger and one TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 415 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 494
Cdd:cd03779    1 GTFLWKITDVSQKQRESSHGRDVSLCSPAFYTAKYGYKVCLRLYLNGDGAGKGTHISLFFVIMKGEYDALLPWPFRHKVT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 568979512 495 LMLMDQgSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVFVAQTVLEN--GTYIKDDTIFIKVIVD 560
Cdd:cd03779   81 FMLLDQ-NNREHVIDAFRPDLSSASFQRPVSDMNVASGCPLFFPLKKLQSpkHAYCKDDTIYIKCVVD 147

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF6 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF6, including the Drosophila protein DTRAF2. TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF6 is the most divergent in its TRAF domain among the mammalian TRAFs. In addition to mediating TNFR family signaling, it is also an essential signaling molecule of the interleukin-1/Toll-like receptor superfamily. Whereas other TRAF molecules display similar and overlapping TNFR-binding specificities, TRAF6 binds completely different sites on receptors such as CD40 and RANK. TRAF6 serves as a molecular bridge between innate and adaptive immunity and plays a central role in osteoimmunology. DTRAF2, as an activator of nuclear factor-kappaB, plays a pivotal role in Drosophila development and innate immunity. TRAF6 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 415 GVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCARVYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVT 494
Cdd:cd03776    1 GIYVWKIKNFSNLRRSMEAGSPVVIHSPGFYTSPPGYKLCARLNLSLPEARCPNYISLFVHLMQGENDSHLDWPFQGTIT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 568979512 495 LMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIAS-GCPVFVAQTVLENGTYIKDDTIFIKVIV 559
Cdd:cd03776   81 LTLLDQSEPRQNIHETMMSKPELLAFQRPTTDRNPKGfGYVEFAHIEDLLQRGFVKNDTLLIKIEV 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 568979512 415 GVLIWKIRDYKRRKQEavmgktlSLYSQPFYTGyfGYKMCARVYLNGDGmGKGTHLSLFFVIMRGEYDaLLPWPFKQKVT 494
Cdd:cd00121    1 GKHTWKIVNFSELEGE-------SIYSPPFEVG--GYKWRIRIYPNGDG-ESGDYLSLYLELDKGESD-LEKWSVRAEFT 69

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 568979512 495 LMLMDQgSSRRHLGDAFKPDPNSssfkkptgEMNIASGCPVFVAQTVLENGTYIKDDTIFIKVIVD 560
Cdd:cd00121   70 LKLVNQ-NGGKSLSKSFTHVFFS--------EKGSGWGFPKFISWDDLEDSYYLVDDSLTIEVEVK 126

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 568979512  47 EDKYKCEKCRLVLCNPKQTECGHRFCESCMAALLS-SSSPKCTACQESIIKDKVF 100
Cdd:cd16642    2 EDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLElNTTPICPIDKETIKSDEVF 56

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 568979512  49 KYKCEKCRLVLCNPKQTECGHRFCESCMAALLSSSSPKCTACQESIIKDKVFKDNCCK 106
Cdd:cd16643    1 KYECPICLMALREPVQTPCGHRFCKACILKSIREAGHKCPVDNEPLLENQLFPDNFAK 58

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 568979512  49 KYKCEKCRLVLCNPKQTECGHRFCESCMAALLSSSSPKCTAC 90
Cdd:cd16639    1 KYLCSDCRNILRRPFQAQCGHRYCSYCLKKILSSGPQKCAAC 42

RIM-binding protein of the cytomatrix active zone; This is a family of proteins that form part of the CAZ (cytomatrix at the active zone) complex which is involved in determining the site of synaptic vesicle fusion. The C-terminus is a PDZ-binding motif that binds directly to RIM (a small G protein Rab-3A effector). The family also contains four coiled-coil domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  243 TNQQikaheaSSAVQHVNLLKEWSNSLEKKVSLLQNES--------------VEKNKSIQSLHNQICSFEIEIERQKEML 308
Cdd:pfam10174 316 TNQN------SDCKQHIEVLKESLTAKEQRAAILQTEVdalrlrleekesflNKKTKQLQDLTEEKSTLAGEIRDLKDML 389

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  309 RNNESKILHLQRVIDSQAEKLKELDKEIrpfrqnweeaDSMKSSVESLQ----NRVTELESVDKSAGQAARNTGLLESQL 384
Cdd:pfam10174 390 DVKERKINVLQKKIENLQEQLRDKDKQL----------AGLKERVKSLQtdssNTDTALTTLEEALSEKERIIERLKEQR 459

                  ....*
gi 568979512  385 SRHDQ 389
Cdd:pfam10174 460 EREDR 464

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 418 IWKIRDYKRrkqeaVMGKTL---SLYSQPFYTGYfGYKMCARVYLNGDGMGKGtHLSLFFVIMRGEYDALLPWPFK-QKV 493
Cdd:cd03782    5 IWHIRNFTQ-----LLATTPpngKIYSPPFLSST-GYSFQVGLYLNGTDDYPG-NLAIYLHLTSGPNDDQLQWPCPwQQA 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 494 TLMLMDQGSS-RRHLG-------DAFK--------------------PDPNSSSFKKPTGemniaSGCPVFVAQTVLENG 545
Cdd:cd03782   78 TMMLLDQHPDiRQRMSnqrsvttDPNMtstdsdeyfwddprkvgsevTDTDGSTFYRGPG-----YGTSAFITHLRLRSR 152

                        170
                 ....*....|
gi 568979512 546 TYIKDDTIFI 555
Cdd:cd03782  153 DFIKGDDVIF 162

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 568979512  50 YKCEKCRLVLCNPKQTECGHRFCESCMAALLSSSSPKCTAC 90
Cdd:cd16449    1 LECPICLERLKDPVLLPCGHVFCRECIRRLLESGSIKCPIC 41

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  267 NSLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEIERqkemlrnneskilhLQRVIDSQAEKLKELDKEIRPFRQNWE-- 344
Cdd:TIGR04523 422 ELLEKEIERLKETIIKNNSEIKDLTNQDSVKELIIKN--------------LDNTRESLETQLKVLSRSINKIKQNLEqk 487

                          90       100
                  ....*....|....*....|..
gi 568979512  345 --EADSMKSSVESLQNRVTELE 364
Cdd:TIGR04523 488 qkELKSKEKELKKLNEEKKELE 509

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 568979512  50 YKCEKCRLVLCNPKQTECGHRFCESCMAALLSSSSPKCTACQ 91
Cdd:cd16542    2 FDCAVCLEVLHQPVRTRCGHVFCRPCIATSLRNNTWTCPYCR 43

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  245 QQIKAhEASSAVQHVNLLKEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEIERQKEMLRNNESKILHLQrvIDS 324
Cdd:TIGR04523 242 NEKTT-EISNTQTQLNQLKDEQNKIKKQLSEKQKELEQNNKKIKELEKQLNQLKSEISDLNNQKEQDWNKELKSE--LKN 318

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 568979512  325 QAEKLKELDKEIrpfRQNWEEADSMKSSVESLQNRVTELES 365
Cdd:TIGR04523 319 QEKKLEEIQNQI---SQNNKIISQLNEQISQLKKELTNSES 356

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 568979512  48 DKYKCEKCRLVLCNPKQTEC-GHRFCESCMAALLSSSSPKCTACQESIIKDKV 99
Cdd:cd16620    2 DELKCPICKDLMKDAVLTPCcGNSFCDECIRTALLEEDFTCPTCKEPDVSPDA 54

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  260 NLLKEWSNSLEKKVSLLQNESVEKNKSIQSLHNQICSfeieIERQKEMLRNNESKIlhlQRVIdsqAEKLKELDKEIRpf 339
Cdd:TIGR04523 310 KELKSELKNQEKKLEEIQNQISQNNKIISQLNEQISQ----LKKELTNSESENSEK---QREL---EEKQNEIEKLKK-- 377

                          90       100
                  ....*....|....*....|....*.
gi 568979512  340 rqnweEADSMKSSVESLQNRVTELES 365
Cdd:TIGR04523 378 -----ENQSYKQEIKNLESQINDLES 398

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 568979512 418 IWKIRDYKRRKQEAVmgKTLSLYSQPFYTGYfGYKMCARVY-LNGDGMGKGTHLSLFFVIMRGEYDALLPWP-FKQKVTL 495
Cdd:cd03783    5 VWRVRNFSQILENTT--KGDVLQSPRFYSPE-GYGYGVSLYpLSNESDYSGNYTGLYFHLCSGENDAVLEWPaLNRQAII 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512 496 MLMDQ--------GSSRRHLGDAFKPDP---NSSSFKKPT--GEMNIASGC--------PVFVAQTVLENGTYIKDDTIF 554
Cdd:cd03783   82 TVLDQdpdvrlrmSSSRSFTTDKSQTSSainGTLRWDRPSrvGTYDTSCDCfrgidfgwSTFISHSQLRRRSFLKNDDLI 161

                 ...
gi 568979512 555 IKV 557
Cdd:cd03783  162 IFV 164

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        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 568979512  48 DKYKCEKCRLVLCNPKQTE-CGHRFCESCMAALLSSSSPKCTACQESIIKDK 98
Cdd:cd16544    1 AELTCPVCQEVLKDPVELPpCRHIFCKACILLALRSSGARCPLCRGPVGKTE 52

RING finger, HC subclass, found in RING finger proteins RNF113A, RNF113B, and similar proteins; RNF113A, also known as zinc finger protein 183 (ZNF183), is an E3 ubiquitin-protein ligase that physically interacts with the E2 protein, UBE2U. A nonsense mutation in RNF113A is associated with an X-linked trichothiodystrophy (TTD). Its yeast ortholog Cwc24p is predicted to have a spliceosome function and acts in a complex with Cef1p to participate in pre-U3 snoRNA splicing, indirectly affecting pre-rRNA processing. It is also important for the U2 snRNP binding to primary transcripts and co-migrates with spliceosomes. Moreover, the ortholog of RNF113A in fruit flies may also act as a spliceosome and is hypothesized to be involved in splicing, namely within the central nervous system. The ortholog in Caenorhabditis elegans is involved in DNA repair of inter-strand crosslinks. RNF113B, also known as zinc finger protein 183-like 1, shows high sequence similarity with RNF113A. Both RNF113A and RNF113B contain a CCCH-type zinc finger, which is commonly found in RNA-binding proteins involved in splicing, and a C3HC4-type RING-HC finger, which is frequently found in E3 ubiquitin ligases.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 568979512  51 KCEKCRLVLCNPKQTECGHRFCESCmAALLSSSSPKCTACQE 92
Cdd:cd16539    7 ACFICRKPFKNPVVTKCGHYFCEKC-ALKHYRKSKKCFVCGK 47

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568979512  51 KCEKCRLVLCNPKQTE-CGHRFCESCMAALLSSSSPKCTACQ-ESIIKDKVFKDNCCKREI 109
Cdd:COG5222  276 KCPLCHCLLRNPMKTPcCGHTFCDECIGTALLDSDFKCPNCSrKDVLLDGLTPDIDKKLEV 336

RING finger, HC subclass, found in RING finger protein 114 (RNF114) and similar proteins; RNF114, also known as zinc finger protein 228 (ZNF228) or zinc finger protein 313 (ZNF313), is a p21(WAF1)-targeting ubiquitin E3 ligase that interacts with X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) and may play a role in p53-mediated cell-fate decisions. It is involved in the immune response to double-stranded RNA in disease pathogenesis. Moreover, RNF114 interacts with A20 and modulates its ubiquitylation. It negatively regulates nuclear factor-kappaB (NF-kappaB)-dependent transcription and positively regulates T-cell activation. RNF114 may play a putative role in the regulation of immune responses, since it corresponds to a novel psoriasis susceptibility gene, ZNF313. RNF114, together with three closely related proteins: RNF125, 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).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 568979512  49 KYKCEKCRLVLCNPKQTECGHRFCESCMAALLSSSSPKCTACQ 91
Cdd:cd16540    1 RFTCPVCLEIFETPVRVPCGHVFCNACLQECLKPKKPVCAVCR 43

RIM-binding protein of the cytomatrix active zone; This is a family of proteins that form part of the CAZ (cytomatrix at the active zone) complex which is involved in determining the site of synaptic vesicle fusion. The C-terminus is a PDZ-binding motif that binds directly to RIM (a small G protein Rab-3A effector). The family also contains four coiled-coil domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  269 LEKKVSLLQNESVEKNKSIQSLHNQ--------------ICSFEIEIERQKEMLRNNESKILHLQRVIDSQ------AEK 328
Cdd:pfam10174 480 LKEKVSALQPELTEKESSLIDLKEHasslassglkkdskLKSLEIAVEQKKEECSKLENQLKKAHNAEEAVrtnpeiNDR 559

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 568979512  329 LKELDKEIRPFRqnwEEADSMKSSVESLQN--RVTELESVDKSAGQAArntglLESQLSRH--DQMLSVHDIRL 398
Cdd:pfam10174 560 IRLLEQEVARYK---EESGKAQAEVERLLGilREVENEKNDKDKKIAE-----LESLTLRQmkEQNKKVANIKH 625

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568979512  268 SLEKKVSLLQNESVEKNKSIQSLHNQICSFEIEI-------ERQKEMLRNNESKILHLQRVIDSQAEKLKELDKEIrpfr 340
Cdd:TIGR04523 444 DLTNQDSVKELIIKNLDNTRESLETQLKVLSRSInkikqnlEQKQKELKSKEKELKKLNEEKKELEEKVKDLTKKI---- 519