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 1907068286  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPICPVDKEVIKPQEVF 94
Cdd:cd16642     1 LEDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLELNTTPICPIDKETIKSDEVF 56

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1907068286 185 ENSCPAYPVSCPNRC-VQTIPRARVNEHL-TVCPEAEQDCPFKHYGCTVKGKRGNLLEH 241
Cdd:pfam02176   2 LETCPFFPIPCPNGCcKKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1907068286  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPICPVDKEVIKPQEVF 94
Cdd:cd16642     1 LEDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLELNTTPICPIDKETIKSDEVF 56

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1907068286 185 ENSCPAYPVSCPNRC-VQTIPRARVNEHL-TVCPEAEQDCPFKHYGCTVKGKRGNLLEH 241
Cdd:pfam02176   2 LETCPFFPIPCPNGCcKKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1907068286  40 EERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPICPVDKEVIKPQEV 93
Cdd:COG5574   213 LADYKCFLCLEEPEVPSCTPCGHLFCLSCLLISWTKKKYEFCPLCRAKVYPKKV 266

Proteobacterial HemX domain, involved in 2-ketogluconate production (unrelated to B. subtilis HemX, COG0755, no evidence of involvement in heme biosynthesis) [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 255 EKNYQLEQRISDLYQSLEQKESKIQQLAETVKKFEKELKQFTQMFGRNGTFLSNVQAL---TSHTDKSAWLEAQVRQLLQ 331
Cdd:COG2959    60 AELAQLAQQLAALQQQAQELRALAQQLQELLQQLAARLAQLEQRLAELQQQLAALQQLlqsLSGSSRDDWLLAEAEYLLR 139

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1907068286 332 IVNQQpSRLDlrslvdavDSVKQRITQLEASDQRL 366
Cdd:COG2959   140 LAGQQ-LQLE--------GDVKTALAALQSADARL 165

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1907068286  44 KCAFCHSVLHNPHQ-TGCGHRFCQQCI-RSLRELNSVPIC 81
Cdd:pfam13923   1 MCPICMDMLKDPSTtTPCGHVFCQDCIlRALRAGNECPLC 40

Vitamin-D-receptor interacting Mediator subunit 4; Members of this family function as part of the Mediator (Med) complex, which links DNA-bound transcriptional regulators and the general transcription machinery, particularly the RNA polymerase II enzyme. They play a role in basal transcription by mediating activation or repression according to the specific complement of transcriptional regulators bound to the promoter.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1907068286 249 HMLLVLEKNYQLEQRISDLYQSLEQKESKIQQLAETVKKFEKELKQ 294
Cdd:pfam10018  16 KTLKELEEHQKNEARILQLRAEAESLDEKIKEIVKTLKEYEKELRA 61

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 1907068286 366 LVLLEGETSKHDAHINIHKAQLNKNEERFKQLEGACYSGKLIWKVTDYRVKKREAVEGHTVSVFSQPFYTSRCGYRLCAR 445
Cdd:cd03777     1 TGLLESQLSRHDQMLSVHDIRLADMDLRFQVLETASYNGVLIWKIRDYKRRKQEAVMGKTLSLYSQPFYTGYFGYKMCAR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 446 AYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVTLMLLDQSGKKNHIVETFKADPNSSSFKRPDGEMNIASGCPRF 525
Cdd:cd03777    81 VYLNGDGMGKGTHLSLFFVIMRGEYDALLPWPFKQKVTLMLMDQGSSRRHLGDAFKPDPNSSSFKKPTGEMNIASGCPVF 160

                         170       180
                  ....*....|....*....|....*...
gi 1907068286 526 VSHSTLENSknTYIKDDTLFLKVAVDLT 553
Cdd:cd03777   161 VAQTVLENG--TYIKDDTIFIKVIVDTS 186

Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF2 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF2 associates with the receptors TNFR-1, TNFR-2, RANK (which mediates differentiation and maturation of osteoclasts) and CD40 (which is important for the proliferation and activation of B cells), among others. It regulates distinct pathways that lead to the activation of nuclear factor-kappaB and Jun NH2-terminal kinases. TRAF2 also indirectly associates with death receptors through its interaction with TRADD (TNFR-associated death domain protein). It is involved in regulating oxidative stress or ROS-induced cell death and in the preconditioning of cells by sublethal stress for protection from subsequent injury. TRAF2 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 386 QLNKNEERFKQLEGACYSGKLIWKVTDYRVKKREAVEGHTVSVFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVV 465
Cdd:cd03778     1 A*ADLEQKVLE*EASTYDGVFIWKISDFARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 466 MRGEFDSLLQWPFRQRVTLMLLDQSGKKnHIVETFKADPNSSSFKRPDGEMNIASGCPRFVSHSTLEnSKNTYIKDDTLF 545
Cdd:cd03778    81 MKGPNDALLRWPFNQKVTLMLLDQNNRE-HVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSK*E-AKNSYVRDDAIF 158

                  ....*.
gi 1907068286 546 LKVAVD 551
Cdd:cd03778   159 IKAIVD 164

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF4 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF4, including the Drosophila protein DTRAF1. TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF4 is highly expressed during embryogenesis, especially in the central and peripheral nervous system. Studies using TRAF4-deficient mice show that TRAF4 is required for neurogenesis, as well as the development of the trachea and the axial skeleton. In addition, TRAF4 augments nuclear factor-kappaB activation triggered by GITR (glucocorticoid-induced TNFR), a receptor expressed in T-cells, B-cells and macrophages. It also participates in counteracting the signaling mediated by Toll-like receptors through its association with TRAF6 and TRIF. DTRAF1 plays a pivotal role in the development of eye imaginal discs and photosensory neuron arrays in Drosophila. TRAF4 contains a RING finger domain, seven zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 404 GKLIWKVTDYRVKKREAVEGHTVSVFSQPFYTSRCGYRLCARAYLNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQRVT 483
Cdd:cd03781     1 GTLLWKITDYSRKLQEAKGRDNLELFSPPFYTHRYGYKLQVSAFLNGNGSGEGSHLSVYIRVLPGEYDNLLEWPFSHRIT 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1907068286 484 LMLLDQS----GKKNHIVETFKADPNSSSFKRP----DGEMNIASGCPRFVSHSTLEnsKNTYIKDDTLFLKVAVD 551
Cdd:cd03781    81 FTLLDQSdpslSKPQHITETFTPDPTWKNFQKPsasrLDESTLGFGYPKFISHEDLK--KRNYIKDDAIFLRASVE 154

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1907068286  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPICPVDKEVIKPQEVF 94
Cdd:cd16642     1 LEDRYKCATCHFVLHNPHQTGCGHRFCQHCILSLLELNTTPICPIDKETIKSDEVF 56

TRAF-type zinc finger;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 128 HLQHCSFQAVPCPNESCREAMLRKDVKEHLSAYCRFREEKCLY----CKRDIVVTNLQDH 183
Cdd:pfam02176   1 HLETCPFFPIPCPNGCCKKKILREDLPDHLELDCPKAEVPCPFkvfgCKEDVKREALQRH 60

TRAF-type zinc finger;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1907068286 185 ENSCPAYPVSCPNRC-VQTIPRARVNEHL-TVCPEAEQDCPFKHYGCTVKGKRGNLLEH 241
Cdd:pfam02176   2 LETCPFFPIPCPNGCcKKKILREDLPDHLeLDCPKAEVPCPFKVFGCKEDVKREALQRH 60

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 1907068286  43 YKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRElNSVPICPVD 84
Cdd:cd16640     1 YKCEKCRLVLCNPKQTECGHRFCESCMNALLS-SSNPQCPAC 41

Meprin family, MATH domain; Meprins are multidomain, highly glycosylated extracellular metalloproteases, which are either anchored to the membrane or secreted into extracellular spaces. They are expressed in renal and intestinal brush border membranes, leukocytes, and cancer cells, and are capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. Meprin proteases are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. Despite their similarity, the two subunits differ in their ability to self-associate, in proteolytic processing during biosynthesis and in substrate specificity. Both subunits are synthesized as membrane spanning proteins, however, the alpha subunit is cleaved during biosynthesis and loses its transmembrane domain. Meprin beta forms homodimers or heterotetramers while meprin alpha oligomerizes into large complexes containing 10-100 subunits. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 427 SVFSQPFYTSRcGYRLCARAYLNGdGSGKGTHLSLYFVVMRGEFDSLLQWP-FRQRVTLMLLDQSGK-KNHI--VETFKA 502
Cdd:cd03771    23 KIYSPRFYSPE-GYAFQVGLYPNG-TESYPGYTGLYFHLCSGENDDVLEWPcPNRQATMTLLDQDPDiQQRMsnQRSFTT 100

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1907068286 503 DPNSSS-----------------FKRPDGEM---NIASGCPRFVSHSTLEnSKNtYIK-DDTLFL 546
Cdd:cd03771   101 DPSMTSsdngeyfwdrpskvgsyDTDTNGCTcyrGPGYGWSTFISHSRLR-RRD-FLKgDDLIIL 163

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 1907068286 407 IWKVTDYRvKKREAVEGHTVsvFSQPFYTSRCGYRLCARAY-LNGDGSGKGTHLSLYFVVMRGEFDSLLQWPFRQR-VTL 484
Cdd:cd03783     5 VWRVRNFS-QILENTTKGDV--LQSPRFYSPEGYGYGVSLYpLSNESDYSGNYTGLYFHLCSGENDAVLEWPALNRqAII 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 485 MLLDQ--------SGKKNHIVETFKADP---NSSSFKRPD--GEMNIASGCPR--------FVSHSTLEnsKNTYIKDDT 543
Cdd:cd03783    82 TVLDQdpdvrlrmSSSRSFTTDKSQTSSainGTLRWDRPSrvGTYDTSCDCFRgidfgwstFISHSQLR--RRSFLKNDD 159

                  ....*
gi 1907068286 544 LFLKV 548
Cdd:cd03783   160 LIIFV 164

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1907068286  40 EERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPICPVDKEVIKPQEV 93
Cdd:COG5574   213 LADYKCFLCLEEPEVPSCTPCGHLFCLSCLLISWTKKKYEFCPLCRAKVYPKKV 266

Proteobacterial HemX domain, involved in 2-ketogluconate production (unrelated to B. subtilis HemX, COG0755, no evidence of involvement in heme biosynthesis) [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 255 EKNYQLEQRISDLYQSLEQKESKIQQLAETVKKFEKELKQFTQMFGRNGTFLSNVQAL---TSHTDKSAWLEAQVRQLLQ 331
Cdd:COG2959    60 AELAQLAQQLAALQQQAQELRALAQQLQELLQQLAARLAQLEQRLAELQQQLAALQQLlqsLSGSSRDDWLLAEAEYLLR 139

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1907068286 332 IVNQQpSRLDlrslvdavDSVKQRITQLEASDQRL 366
Cdd:COG2959   140 LAGQQ-LQLE--------GDVKTALAALQSADARL 165

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 1907068286  43 YKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPiCPVD 84
Cdd:cd16449     1 LECPICLERLKDPVLLPCGHVFCRECIRRLLESGSIK-CPIC 41

Modified RING finger, HC subclass (C3HC3D-type), found in ligand of Numb protein LNX1, LNX2, and similar proteins; The ligand of Numb protein X (LNX) family, also known as PDZ and RING (PDZRN) family, includes LNX1-5, which can interact with Numb, a key regulator of neurogenesis and neuronal differentiation. LNX5 (also known as PDZK4 or PDZRN4L) shows high sequence homology to LNX3 and LNX4, but it lacks the RING domain. LNX1-4 proteins function as E3 ubiquitin ligases and have a unique domain architecture consisting of an N-terminal RING-HC finger for E3 ubiquitin ligase activity and either two or four PDZ domains necessary for substrate-binding. LNX1/LNX2-like proteins contain a modified C3HC3D-type RING-HC finger and four PDZ domains. This model corresponds to the RING finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1907068286  42 RYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLreLNSVPICPVDK 85
Cdd:cd16637     1 DLTCHICLQPLVEPLDTPCGHTFCYKCLTNY--LKIQQCCPLDR 42

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 1907068286  45 CAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPI-CPVDKEVI 88
Cdd:cd16498    19 CPICLELLKEPVSTKCDHQFCRFCILKLLQKKKKPApCPLCKKSV 63

RING finger, HC subclass, found in tripartite motif-containing protein 35 (TRIM35) and similar proteins; TRIM35, also known as hemopoietic lineage switch protein 5 (HLS5), is a putative hepatocellular carcinoma (HCC) suppressor that inhibits phosphorylation of pyruvate kinase isoform M2 (PKM2), which is involved in aerobic glycolysis of cancer cells and further suppresses the Warburg effect and tumorigenicity in HCC. It also negatively regulates Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon production by suppressing the stability of interferon regulatory factor 7 (IRF7). Moreover, TRIM35 regulates erythroid differentiation by modulating globin transcription factor 1 (GATA-1) activity. TRIM35 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1907068286  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRELNSVPICPVDKEVIKPQE 92
Cdd:cd16599     1 FKEELLCPICYEPFREAVTLRCGHNFCKGCVSRSWERQPRAPCPVCKEASSSDD 54

RING finger, HC subclass, found in ligand of Numb protein LNX3, LNX4, and similar proteins; The ligand of Numb protein X (LNX) family, also known as PDZ and RING (PDZRN) family, includes LNX1-5, which can interact with Numb, a key regulator of neurogenesis and neuronal differentiation. LNX5 (also known as PDZK4, or PDZRN4L) shows high sequence homology to LNX3 and LNX4, but it lacks the RING domain. LNX1-4 proteins function as E3 ubiquitin ligases and have a unique domain architecture consisting of an N-terminal RING-HC finger for E3 ubiquitin ligase activity and either two or four PDZ domains necessary for the substrate-binding. This family corresponds to LNX3/LNX4-like proteins, which contains a C3HC4-type RING-HC finger and two PDZ domains.

                          10        20
                  ....*....|....*....|....*.
gi 1907068286  44 KCAFCHSVLHNPHQTGCGHRFCQQCI 69
Cdd:cd16512     2 KCKLCLGVLEEPLATPCGHVFCAGCV 27

RING finger, HC subclass, found in tripartite motif-containing protein 26 (TRIM26) and similar proteins; TRIM26, also known as acid finger protein (AFP), RING finger protein 95 (RNF95), or zinc finger protein 173 (ZNF173), is an E3 ubiquitin-protein ligase that negatively regulates interferon-beta production and antiviral response through polyubiquitination and degradation of nuclear transcription factor IRF3. It functions as an important regulator for RNA virus-triggered innate immune response by bridging TBK1 to NEMO (NF-kappaB essential modulator, also known as IKKgamma) and mediating TBK1 activation. It also acts as a novel tumor suppressor of hepatocellular carcinoma by regulating cancer cell proliferation, colony forming ability, migration, and invasion. TRIM26 belongs 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, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1907068286  39 LEERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLREL---NSVPICPV 83
Cdd:cd16598     1 LEEEVTCSICLDYLRDPVTIDCGHNFCRSCITDYCPIsggHERPVCPL 48

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1907068286  41 ERYKCAFCHSVLHNPHQ-TGCGHRFCQQCIRSLRELN-SVPICPVDKEVIK 89
Cdd:cd16554     1 ESLTCPVCLDLYYDPYMcYPCGHIFCEPCLRQLAKSSpKNTPCPLCRTTIR 51

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1907068286  43 YKCAFCHSVLHNPHQTGCGHRFCQQCI-RSLRELNSVPIC 81
Cdd:cd16504     3 FLCPICFDIIKEAFVTKCGHSFCYKCIvKHLEQKNRCPKC 42

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 1907068286  44 KCAFCHSVLHNPHQTGCGHRFCQQCIRslRELNSVPICPVDK 85
Cdd:cd23148     5 RCHICKDLLKAPMRTPCNHTFCSFCIR--THLNNDARCPLCK 44

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 1907068286  41 ERYKCAFCHSVLHNPHQTGC-GHRFCQQCIRSLReLNSVPICPVDKEVIKP 90
Cdd:cd16620     2 DELKCPICKDLMKDAVLTPCcGNSFCDECIRTAL-LEEDFTCPTCKEPDVS 51

Exopolysaccharide export protein/domain GumC/Wzc1 [Cell wall/membrane/envelope biogenesis];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907068286 257 NYQLEQRISDLYQSLEQKESKIQQLAETVKKFEKELKQFTQmfgRNGTF------------LSNVQA-LTSHTDKSAWLE 323
Cdd:COG3206   163 EQNLELRREEARKALEFLEEQLPELRKELEEAEAALEEFRQ---KNGLVdlseeaklllqqLSELESqLAEARAELAEAE 239

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907068286 324 AQVRQLLQIVNQQPSRLDLRSLVDAVDSVKQRITQLEAsdQRLVLLEGETSKHDAHINIhKAQLNKNEERFKQ 396
Cdd:COG3206   240 ARLAALRAQLGSGPDALPELLQSPVIQQLRAQLAELEA--ELAELSARYTPNHPDVIAL-RAQIAALRAQLQQ 309

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1907068286  45 CAFCHSVLHNPHQTGCGHRFCQQCIRslRELNSVPICPVDKEVI 88
Cdd:cd16514     4 CSLCLRLLYEPVTTPCGHTFCRACLE--RCLDHSPKCPLCRTSL 45

RING finger, HC subclass, found in tripartite motif-containing protein 39 (TRIM39) and similar proteins; TRIM39, also known as RING finger protein 23 (RNF23) or testis-abundant finger protein, is an E3 ubiquitin-protein ligase that plays a role in controlling DNA damage-induced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others. TRIM39 also functions as a regulator of several key processes in the proliferative cycle. It directly regulates p53 stability. It modulates cell cycle progression and DNA damage responses via stabilizing p21. Moreover, TRIM39 negatively regulates the nuclear factor kappaB (NFkappaB)-mediated signaling pathway through stabilization of Cactin, an inhibitor of NFkappaB- and Toll-like receptor (TLR)-mediated transcription, which is induced by inflammatory stimulants such as tumor necrosis factor alpha. Furthermore, TRIM39 is a MOAP-1-binding protein that can promote apoptosis signaling through stabilization of MOAP-1 via the inhibition of its poly-ubiquitination process. TRIM39 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1907068286  45 CAFCHSVLHNPHQTGCGHRFCQQCI-RSLRELNSVPICPV 83
Cdd:cd16601     4 CSLCKEYLKDPVIIECGHNFCRACItRFWEELDGDFPCPQ 43

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1907068286  40 EERYKCAFCHSVLHNPHQTGCGHRFCQQCIRSLRE-LNSVPICPVDKEVIKP 90
Cdd:cd16543     1 EDQLTCSICLDLLKDPVTIPCGHSFCMNCITLLWDrKQGVPSCPQCRESFPP 52

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1907068286  45 CAFCHSVLHNPHQT-GCGHRFCQQCIRSLreLNSVPICPVDK 85
Cdd:cd16634     4 CPICSGVLEEPLQApHCEHAFCNACITEW--LSRQQTCPVDR 43

second 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 second one.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1907068286  38 QLEERYKCAFCHSVLHNPHQTGCGHRFCQQCI-----------------RSLRELNSVPICP 82
Cdd:cd23139     1 RLLKEFGCQICKKVLSLPVSTPCGHNFCKACLeakfagiadvrdrgnggRSLRARKNVKPCP 62