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 528480755 365 QLAESEQSLRELQFCTYDGVFIWKIAEFSRRRQDAVAGRAPAMFSPAFYSSKYGYKMCLRLYLNGDGTGRGSHLSLFFVV 444
Cdd:cd03778    1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 528480755 445 MKGKYDALLKWPFSQKVTLMLLDQNNREHIIDAFRPDVSSTSFQRPISEMNIASGCPLFCPLAKLAGKSSYLRDDTIFIK 524
Cdd:cd03778   81 MKGPNDALLRWPFNQKVTLMLLDQNNREHVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*EAKNSYVRDDAIFIK 160

                 ....
gi 528480755 525 AIVD 528
Cdd:cd03778  161 AIVD 164

RING finger (Really Interesting New Gene) domain and U-box domain superfamily; 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 different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are 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 enable efficient transfer of ubiquitin from E2 to the substrates.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 528480755  42 KYQCQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIPCEAC 83
Cdd:cd16639    1 KYLCSDCRNILRRPFQAQCGHRYCSYCLKKILSSGPQKCAAC 42

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 528480755 365 QLAESEQSLRELQFCTYDGVFIWKIAEFSRRRQDAVAGRAPAMFSPAFYSSKYGYKMCLRLYLNGDGTGRGSHLSLFFVV 444
Cdd:cd03778    1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 528480755 445 MKGKYDALLKWPFSQKVTLMLLDQNNREHIIDAFRPDVSSTSFQRPISEMNIASGCPLFCPLAKLAGKSSYLRDDTIFIK 524
Cdd:cd03778   81 MKGPNDALLRWPFNQKVTLMLLDQNNREHVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*EAKNSYVRDDAIFIK 160

                 ....
gi 528480755 525 AIVD 528
Cdd:cd03778  161 AIVD 164

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 528480755  42 KYQCQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIPCEAC 83
Cdd:cd16639    1 KYLCSDCRNILRRPFQAQCGHRYCSYCLKKILSSGPQKCAAC 42

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 528480755  189 HDEICQKFPMQCKD-CGKKKIPREKFQEHTK-SCAKSKSACQFREIGCRAVVDNCKQQEH 246
Cdd:pfam02176   1 HLETCPFFPIPCPNgCCKKKILREDLPDHLElDCPKAEVPCPFKVFGCKEDVKREALQRH 60

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

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 528480755  45 CQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIpCEACRAE 86
Cdd:COG5432   28 CRICDCRISIPCETTCGHTFCSLCIRRHLGTQPF-CPVCRED 68

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 528480755   45 CQQCKDILRKPFQA-QCGHRFCVFCFKQLTSSGPIPCEAC 83
Cdd:pfam00097   1 CPICLEEPKDPVTLlPCGHLFCSKCIRSWLESGNVTCPLC 40

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 528480755 365 QLAESEQSLRELQFCTYDGVFIWKIAEFSRRRQDAVAGRAPAMFSPAFYSSKYGYKMCLRLYLNGDGTGRGSHLSLFFVV 444
Cdd:cd03778    1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 528480755 445 MKGKYDALLKWPFSQKVTLMLLDQNNREHIIDAFRPDVSSTSFQRPISEMNIASGCPLFCPLAKLAGKSSYLRDDTIFIK 524
Cdd:cd03778   81 MKGPNDALLRWPFNQKVTLMLLDQNNREHVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*EAKNSYVRDDAIFIK 160

                 ....
gi 528480755 525 AIVD 528
Cdd:cd03778  161 AIVD 164

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 528480755 383 GVFIWKIAEFSRRRQDAVAGRAPAMFSPAFYSSKYGYKMCLRLYLNGDGTGRGSHLSLFFVVMKGKYDALLKWPFSQKVT 462
Cdd:cd00270    1 GVLIWKIKDYSRKLQEAVAGSNTVLYSPPFYTSRYGYKLCLRLYLNGDGTGKGTHLSLFVHVMKGEYDALLEWPFRGKIT 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 528480755 463 LMLLDQNN---REHIIDAFRPDVSSTSFQ-RPISEMNIASGCPLFCPLAKLAgKSSYLRDDTIFIKAIVD 528
Cdd:cd00270   81 LTLLDQSDdskRKHITETFMPDPNSSAFQrPPTGENNIGFGYPEFVPLEKLE-SRGYVKDDTLFIKVEVD 149

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 528480755 383 GVFIWKIAEFSRRRQDAVAGRAPAMFSPAFYSSKYGYKMCLRLYLNGDGTGRGSHLSLFFVVMKGKYDALLKWPFSQKVT 462
Cdd:cd03780    1 GKLIWKVTDYKMKKKEAVDGHTVSIFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 528480755 463 LMLLDQNN-REHIIDAFRPDVSSTSFQRPISEMNIASGCPLFCPLAKLA-GKSSYLRDDTIFIKAIVD 528
Cdd:cd03780   81 LMLLDQSGkKNHIMETFKADPNSSSFKRPDGEMNIASGCPRFVAHSVLEnAKNTYIKDDTLFLKVAVD 148

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 528480755 383 GVFIWKIAEFSRRRQDAVAGRAPAMFSPAFYSSKYGYKMCLRLYLNGDGTGRGSHLSLFFVVMKGKYDALLKWPFSQKVT 462
Cdd:cd03776    1 GIYVWKIKNFSNLRRSMEAGSPVVIHSPGFYTSPPGYKLCARLNLSLPEARCPNYISLFVHLMQGENDSHLDWPFQGTIT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 528480755 463 LMLLDQNN-REHIIDAF--RPDVSstSFQRPISEMNIAS-GCPLFCPLAKLAgKSSYLRDDTIFIKAIV 527
Cdd:cd03776   81 LTLLDQSEpRQNIHETMmsKPELL--AFQRPTTDRNPKGfGYVEFAHIEDLL-QRGFVKNDTLLIKIEV 146

TNF receptor-associated factor BIRC3 binding domain; This domain is found in TNF receptor-associated factor 1 and 2 (TRAF1 and TRAF2), where it binds to Baculoviral IAP repeat-containing protein 3 (BIRC3) (cIAP2).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 528480755  307 QKKVTTLENIVCVLNKEVERSALTMEAISRQHRLDQEKIENLSNKVRQLERTLT 360
Cdd:pfam16673  10 ENKVATFENIVAVLNREVERCSTTIEAYERQRRLDQDKIESLENKIRQLERSIA 63

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 528480755   384 VFIWKIAEFSRRRQDavagraPAMFSPAFYSskYGYKMCLRLYLNGDgtgrgsHLSLFFVVMKGKYDALlKWPFSQKVTL 463
Cdd:smart00061   1 VLSHTFKNVSRLEEG------ESYFSPSEEH--FNIPWRLKIYRKNG------FLSLYLHCEKEECDSR-KWSIEAEFTL 65

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 528480755   464 MLLDQNNREHiidafrPDVSSTSFQRPISemniaSGCPLFC 504
Cdd:smart00061  66 KLVSQNGKSL------SKKDKHVFEKPSG-----WGFSKFI 95

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 528480755 385 FIWKIAEFSRRRQDAVAGRApaMFSPAFYSSKyGYKMCLRLYLNGDgTGRGSHLSLFFVVMKGKYDALLKWPFS-QKVTL 463
Cdd:cd03782    4 HIWHIRNFTQLLATTPPNGK--IYSPPFLSST-GYSFQVGLYLNGT-DDYPGNLAIYLHLTSGPNDDQLQWPCPwQQATM 79

                 ....*.
gi 528480755 464 MLLDQN 469
Cdd:cd03782   80 MLLDQH 85

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 528480755 386 IWKIAEFSRRRQDAVAGraPAMFSPAFYSSKyGYKMCLRLY-LNGDGTGRGSHLSLFFVVMKGKYDALLKWP-FSQKVTL 463
Cdd:cd03783    5 VWRVRNFSQILENTTKG--DVLQSPRFYSPE-GYGYGVSLYpLSNESDYSGNYTGLYFHLCSGENDAVLEWPaLNRQAII 81

                         90       100
                 ....*....|....*....|....*....
gi 528480755 464 MLLDQNnrehiidafrPDV-----SSTSF 487
Cdd:cd03783   82 TVLDQD----------PDVrlrmsSSRSF 100

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

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 528480755  40 EPKYQCQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIP-CEACRAE 86
Cdd:cd23125    2 EEKYLCCNCKNVLKKAQQTLCGHRYCLACLSWIVRNNKNPiCQKCKEE 49

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 528480755  42 KYQCQQCKDILRKPFQAQCGHRFCVFC-FKQLTSSGPipceACRAEGIFEEETSVlniavaFPDNAAR 108
Cdd:cd16643    1 KYECPICLMALREPVQTPCGHRFCKACiLKSIREAGH----KCPVDNEPLLENQL------FPDNFAK 58

RING finger, HC subclass, found in tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) and similar proteins; TRAF3, also known as CAP-1, CD40 receptor-associated factor 1 (CRAF1), CD40-binding protein (CD40BP), or LMP1-associated protein 1 (LAP1), is a member of the TRAF protein family, which mainly functions in the immune system, where it mediates signaling through tumor necrosis factor receptors (TNFRs) and interleukin-1/Toll-like receptors (IL-1/TLRs). It also plays a unique cell type-specific and critical role in the restraint of B-cell homeostatic survival, a role with important implications for both B-cell differentiation and the pathogenesis of B-cell malignancies. TRAF3 differentially regulates differentiation of specific T cell subsets. It is required for iNKT cell development, restrains Treg cell development in the thymus, and plays an essential role in the homeostasis of central memory CD8+ T cells. TRAF3 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 528480755  43 YQCQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIPCEAC 83
Cdd:cd16640    1 YKCEKCRLVLCNPKQTECGHRFCESCMNALLSSSNPQCPAC 41

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

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 528480755  45 CQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIpCEACRAE 86
Cdd:COG5432   28 CRICDCRISIPCETTCGHTFCSLCIRRHLGTQPF-CPVCRED 68

RING finger, HC subclass, found in tripartite motif-containing protein TRIM4 and similar proteins; TRIM4 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM4, also known as RING finger protein 87 (RNF87), is a cytoplasmic E3 ubiquitin-protein ligase that has recently evolved and is present only in higher mammals. It transiently interacts with mitochondria, induces mitochondrial aggregation and sensitizes the cells to hydrogen peroxide (H2O2) induced death. Its interaction with peroxiredoxin 1 (PRX1) is critical for the regulation of H2O2 induced cell death. Moreover, TRIM4 functions as a positive regulator of RIG-I-mediated type I interferon induction. It regulates the K63-linked ubiquitination of RIG-1 and assembly of antiviral signaling complex at the mitochondria.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 528480755  39 MEPKYQCQQCKDILRKPFQAQCGHRFCVFCFKQ--LTSSGPIPCEACR 84
Cdd:cd16590    3 IQEELTCPICLDYFQDPVSIECGHNFCRGCLHRnwAPGGGPFPCPECR 50

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

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                 ....*....|....*....|....*....|....*....|..
gi 528480755  44 QCQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIPCEACRA 85
Cdd:cd23138    4 NCSFCMQLPERPVTTPCGHNFCLKCFQKWMGQGKKTCGTCRS 45

RING finger, HC subclass, found in RING finger protein 180 (RNF180) and similar proteins; RNF180, also known as Rines, is a membrane-bound E3 ubiquitin-protein ligase well conserved among vertebrates. It is a critical regulator of the monoaminergic system, as well as emotional and social behavior. It interacts with brain monoamine oxidase A (MAO-A) and targets it for ubiquitination and degradation. It also functions as a novel tumor suppressor in gastric carcinogenesis. The hypermethylated CpG site count of the RNF180 DNA promoter can be used to predict survival of gastric cancer. RNF180 contains a novel conserved dual specificity protein phosphatase Rines conserved (DSPRC) domain, a basic coiled-coil domain, a C3HC4-type RING-HC finger, and a C-terminal hydrophobic region that is predicted to be a transmembrane domain.

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                 ....*....|....*....|....*....|....*....|....*
gi 528480755  43 YQCQQCKDILRKPFQAQ-CGHRFCVFCFKQLTSSGP--IPCEACR 84
Cdd:cd16554    3 LTCPVCLDLYYDPYMCYpCGHIFCEPCLRQLAKSSPknTPCPLCR 47

RING finger, HC subclass, found in tripartite motif-containing protein 77 (TRIM77) and similar proteins; TRIM77 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 two consecutive zinc-binding domains, a C3HC4-type RING-HC finger and Bbox2, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain.

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                 ....*....|....*....|....*....|....*....|....*....
gi 528480755  40 EPKYQCQQCKDILRKPFQAQCGHRFCVFCFKQL--TSSGPIPCEACRAE 86
Cdd:cd16543    1 EDQLTCSICLDLLKDPVTIPCGHSFCMNCITLLwdRKQGVPSCPQCRES 49

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.

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                 ....*....|....*....|....*....|....*....|...
gi 528480755  43 YQCQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIPCEACRA 85
Cdd:cd16542    2 FDCAVCLEVLHQPVRTRCGHVFCRPCIATSLRNNTWTCPYCRA 44

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.

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                  ....*....|....*....|....*....|....*....|
gi 528480755   45 CQQCKDILRKPFQA-QCGHRFCVFCFKQLTSSGPIPCEAC 83
Cdd:pfam00097   1 CPICLEEPKDPVTLlPCGHLFCSKCIRSWLESGNVTCPLC 40

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).

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                 ....*....|....*....|....*....|....*....|...
gi 528480755  42 KYQCQQCKDILRKPFQAQCGHRFCVFCFKQLTSSGPIPCEACR 84
Cdd:cd16540    1 RFTCPVCLEIFETPVRVPCGHVFCNACLQECLKPKKPVCAVCR 43

RING finger, HC subclass, found in RING finger protein 112 (RNF112) and similar proteins; RNF112, also known as brain finger protein (BFP), zinc finger protein 179 (ZNF179), or neurolastin, is a peripheral membrane protein that is predominantly expressed in the central nervous system and localizes to endosomes. It contains functional GTPase and C3HC4-type RING-HC finger domains and has been identified as a brain-specific dynamin family GTPase that affects endosome size and spine density. Moreover, RNF112 acts as a downstream target of sigma-1 receptor (Sig-1R) regulation and may play a novel role in neuroprotection by mediating the neuroprotective effects of dehydroepiandrosterone (DHEA) and its sulfated analog (DHEAS).

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                 ....*....|....*....|....*....|....*....|..
gi 528480755  45 CQQCKDILRKPFQAQCGHRFCVFCFK--QLTSSGPIPCEACR 84
Cdd:cd16538    5 CSICLERLREPISLDCGHDFCIRCFSthRIPGCEPPCCPECR 46

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM41, TRIM52 and similar proteins; TRIM41 and TRIM52, two closely related tripartite motif-containing proteins, have dramatically expanded RING domains compared with the rest of the TRIM family proteins. TRIM41 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. In contrast, TRIM52 lacks the putative viral recognition SPRY/B30.2 domain, and thus has been classified to the C-V subclass of the TRIM family that contains only RBCC domains. TRIM41, also known as RING finger-interacting protein with C kinase (RINCK), is an E3 ubiquitin-protein ligase that promotes the ubiquitination of protein kinase C (PKC) isozymes in cells. It specifically recognizes the C1 domain of PKC isozymes. It controls the amplitude of PKC signaling by controlling the amount of PKC in the cell. TRIM52, also known as RING finger protein 102 (RNF102), is encoded by a novel, noncanonical antiviral TRIM52 gene in primate genomes with unique specificity determined by the rapidly evolving RING domain.

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                 ....*....|....*....|....*....|....*....|
gi 528480755  45 CQQCKDILRKPFQAQCGHRFCVFCFKQLTSsgpIPCEACR 84
Cdd:cd16602    6 CAICLDYFKDPVSIGCGHNFCRVCVTQLWG---FTCPQCR 42

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

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                 ....*....|....*....|....*....|
gi 528480755  39 MEPKYQCQQCKDILRKPFQAQCGHRFCVFC 68
Cdd:cd16718    1 VDPDFKCNLCNKVLEDPLTTPCGHVFCAGC 30