Zinc-ribbon; This is a typical zinc-ribbon finger, with each pair of zinc-ligands coming from more-or-less either side of two knuckles. It is found in eukaryotes.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 186478634  1194 GDMQVYFRMLDALLAEQKMPDEYLNQTQVILCNDCGRKGNAPYHWLYHKCSSCASYNTR 1252
Cdd:pfam14599    1 VDMEAYWRALDAEIAAQPMPEEYANWRVVILCNDCEAKSEVPFHFLGLKCSHCGSYNTR 59

Hemerythrin-like domain; Hemerythrin (Hr) like domains have the same four alpha helix bundle and a similar, but slightly different active site structure than hemerythrin. They are non-heme diiron binding proteins mainly found in bacteria and eukaryotes. Like Hr, they may be involved in oxygen transport or like human FBXL5 (F-box and leucine-rich repeat protein 5), a member of this group, play a role in cellular iron homeostasis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634  613 DLIFYFHKAMKKDLDYLVRGSARLATDY-SFLGEFQQRFHLIKFLYQIHSDAEDEIAFPALEAKGKLQNISQSYSIDHEL 691
Cdd:cd12108     1 DLLKLEHRAIRRELGRLARLAGALAAGGpDDARALAERFRFLATELHHHHTAEEELLFPALRERVPLAAVLDALEAEHAE 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634  692 EVEHLNKVSFLLNELAELNMLVLDhknvkyeklcmSLQDICKSIHKLLSEHLHREETELW 751
Cdd:cd12108    81 IDELLARLEALLPALLAGDAEDAE-----------ELAAALEALRTALREHLDEEEEELF 129

RING finger, H2 subclass, found in p53-induced RING-H2 protein (Pirh2) and similar proteins; Pirh2, also known as RING finger and CHY zinc finger domain-containing protein 1 (Rchy1), androgen receptor N-terminal-interacting protein, CH-rich-interacting match with PLAG1, RING finger protein 199 (RNF199), or zinc finger protein 363 (ZNF363), is a p53 inducible E3 ubiquitin-protein ligase that functions as a negative regulator of p53. It preferably ubiquitylates the tetrameric form of p53 in vitro and in vivo, suggesting a role of Pirh2 in downregulating the transcriptionally active form of p53 in the cell. Moreover, Pirh2 inhibits the transcriptional activity of p73, a homolog of the tumor suppressor p53, by promoting its ubiquitination. It also monoubiquitinates DNA polymerase eta (PolH) to suppress translesion DNA synthesis. Furthermore, Pirh2 functions as a negative regulator of the cyclin-dependent kinase inhibitor p27(Kip1) function by promoting ubiquitin-dependent proteasomal degradation. Pirh2 enhances androgen receptor (AR) signaling through inhibition of histone deacetylase 1 (HDAC1) and is overexpressed in prostate cancer. It interacts with TIP60 and this association may regulate Pirh2 stability. In addition, the oncoprotein pleomorphic adenoma gene like 2 (PLAGL2) can bind to the Pirh2 dimer and therefore control the stability of Pirh2. Pirh2 contains a total of nine zinc-binding sites with six located at the N-terminal region, two in the C3H2C3-type RING-H2 domain, and one in the C-terminal region. Nine zinc binding sites comprise three different zinc coordination schemes, including RING type cross-brace zinc coordination, C4 zinc finger, and a novel left-handed beta-spiral zinc-binding motif formed by three recurrent CCHC sequence motifs. This subfamily also includes Drosophila melanogaster Deltex, a ubiquitously expressed cytoplasmic ubiquitin E3 ligase that mediates Notch activation in Drosophila. It selectively suppresses T-cell activation through degradation of a key signaling molecule, MAP kinase kinase kinase 1 (MEKK1). It also inhibits Jun-mediated transcription at the stage of Ras-dependent Jun N-terminal protein kinase (JNK) activation. Deltex contains N-terminal two Notch-binding WWE domains that physically interact with the Notch ankyrin domains, a proline-rich motif that shares homology with SH3-binding domains, and a RING finger at the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 186478634 1147 NCPICHEYIFTSNSPVKALPCGHVMHSTCFQEYTCSH-YTCPICS 1190
Cdd:cd16464     1 NCPVCLEDLFTSREPVHVLPCGHLMHSTCFEEYLKSGnYRCPLCS 45

Zinc-ribbon; This is a typical zinc-ribbon finger, with each pair of zinc-ligands coming from more-or-less either side of two knuckles. It is found in eukaryotes.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 186478634  1194 GDMQVYFRMLDALLAEQKMPDEYLNQTQVILCNDCGRKGNAPYHWLYHKCSSCASYNTR 1252
Cdd:pfam14599    1 VDMEAYWRALDAEIAAQPMPEEYANWRVVILCNDCEAKSEVPFHFLGLKCSHCGSYNTR 59

Hemerythrin-like domain; Hemerythrin (Hr) like domains have the same four alpha helix bundle and a similar, but slightly different active site structure than hemerythrin. They are non-heme diiron binding proteins mainly found in bacteria and eukaryotes. Like Hr, they may be involved in oxygen transport or like human FBXL5 (F-box and leucine-rich repeat protein 5), a member of this group, play a role in cellular iron homeostasis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634  613 DLIFYFHKAMKKDLDYLVRGSARLATDY-SFLGEFQQRFHLIKFLYQIHSDAEDEIAFPALEAKGKLQNISQSYSIDHEL 691
Cdd:cd12108     1 DLLKLEHRAIRRELGRLARLAGALAAGGpDDARALAERFRFLATELHHHHTAEEELLFPALRERVPLAAVLDALEAEHAE 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634  692 EVEHLNKVSFLLNELAELNMLVLDhknvkyeklcmSLQDICKSIHKLLSEHLHREETELW 751
Cdd:cd12108    81 IDELLARLEALLPALLAGDAEDAE-----------ELAAALEALRTALREHLDEEEEELF 129

RING finger, H2 subclass, found in p53-induced RING-H2 protein (Pirh2) and similar proteins; Pirh2, also known as RING finger and CHY zinc finger domain-containing protein 1 (Rchy1), androgen receptor N-terminal-interacting protein, CH-rich-interacting match with PLAG1, RING finger protein 199 (RNF199), or zinc finger protein 363 (ZNF363), is a p53 inducible E3 ubiquitin-protein ligase that functions as a negative regulator of p53. It preferably ubiquitylates the tetrameric form of p53 in vitro and in vivo, suggesting a role of Pirh2 in downregulating the transcriptionally active form of p53 in the cell. Moreover, Pirh2 inhibits the transcriptional activity of p73, a homolog of the tumor suppressor p53, by promoting its ubiquitination. It also monoubiquitinates DNA polymerase eta (PolH) to suppress translesion DNA synthesis. Furthermore, Pirh2 functions as a negative regulator of the cyclin-dependent kinase inhibitor p27(Kip1) function by promoting ubiquitin-dependent proteasomal degradation. Pirh2 enhances androgen receptor (AR) signaling through inhibition of histone deacetylase 1 (HDAC1) and is overexpressed in prostate cancer. It interacts with TIP60 and this association may regulate Pirh2 stability. In addition, the oncoprotein pleomorphic adenoma gene like 2 (PLAGL2) can bind to the Pirh2 dimer and therefore control the stability of Pirh2. Pirh2 contains a total of nine zinc-binding sites with six located at the N-terminal region, two in the C3H2C3-type RING-H2 domain, and one in the C-terminal region. Nine zinc binding sites comprise three different zinc coordination schemes, including RING type cross-brace zinc coordination, C4 zinc finger, and a novel left-handed beta-spiral zinc-binding motif formed by three recurrent CCHC sequence motifs. This subfamily also includes Drosophila melanogaster Deltex, a ubiquitously expressed cytoplasmic ubiquitin E3 ligase that mediates Notch activation in Drosophila. It selectively suppresses T-cell activation through degradation of a key signaling molecule, MAP kinase kinase kinase 1 (MEKK1). It also inhibits Jun-mediated transcription at the stage of Ras-dependent Jun N-terminal protein kinase (JNK) activation. Deltex contains N-terminal two Notch-binding WWE domains that physically interact with the Notch ankyrin domains, a proline-rich motif that shares homology with SH3-binding domains, and a RING finger at the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 186478634 1147 NCPICHEYIFTSNSPVKALPCGHVMHSTCFQEYTCSH-YTCPICS 1190
Cdd:cd16464     1 NCPVCLEDLFTSREPVHVLPCGHLMHSTCFEEYLKSGnYRCPLCS 45

Hemerythrin HHE cation binding domain; Iteration of the HHE family found it to be related to Hemerythrin. It also demonstrated that what has been described as a single domain in fact consists of two cation binding domains. Members of this family occur all across nature and are involved in a variety of processes. For instance, in Nereis diversicolor Swiss:P80255 binds Cadmium so as to protect the organizm from toxicity. However Hemerythrin is classically described as Oxygen-binding through two attached Fe2+ ions. And the bacterial Swiss:Q7WX96 is a regulator of response to NO, which suggests yet another set-up for its metal ligands. In Staphylococcus aureus P72360 has been noted to be important when the organizm switches to living in environments with low oxygen concentrations; perhaps this protein acts as an oxygen store or scavenger. This domain can bind oxygen (Matilla et.al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043)

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634    44 PILLFVYFHKAFRAQLAELQFLAGDTVRSGSDLAVELrskFEFLKLVYKYHSAAEDEVIFSALDTRVKNIVFNYSL---E 120
Cdd:pfam01814    2 IIELLDAEHRRLRELLALLRALADALGDSHLRKLAEL---LDELVDELEAHHAAEEELLFPALERRSPGGEAPIEVlrkE 78

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 186478634   121 HDATDDLFTSVFHWLNVLEEEQGNRADvlrevvlcIGTIQSSICQHMLKEERQVFPL 177
Cdd:pfam01814   79 HDEIRELLEELEALLKGAEPGAAFAEL--------LEALAEWLREHIAKEEEVLFPL 127

Hemerythrin domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634   52 HKAFRAQLAELQFLAgDTVRSGSDLAVE-LRSKFEFLKlVY--KYHSAAEDEVIFSAL---DTRVKNIVFNYSLEHDATD 125
Cdd:COG3945    11 HRNIRRLLAVLEKLL-DRLEEGEEVDFElLRDILDYIR-EFadRCHHPKEEDILFPRLeerGGEAAGPIAVLLAEHEQGR 88

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 186478634  126 DLFTSVFHWLN-VLEEEQGNRADVLREVVLCIGTIQssicQHMLKEERQVFPLMIENFSFEEQASL 190
Cdd:COG3945    89 QLTRELEEALEaYLAGDVVARDELAAALRAYIALLR----QHIAKEENVLFPLAERLLSDEDWEEL 150

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634 1148 CPICHEYIFTS---------NSPVKALPCGHVMHSTCFQEYTCSHYTCPICSKSL-GDMQ 1197
Cdd:COG5243   290 CTICMDEMFHPdheplprglDMTPKRLPCGHILHLHCLKNWLERQQTCPICRRPViFDQS 349

Zinc-ribbon; This is a typical zinc-ribbon finger, with each pair of zinc-ligands coming from more-or-less either side of two knuckles. It is found in eukaryotes.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 186478634  1194 GDMQVYFRMLDALLAEQKMPDEYLNQTQVILCNDCGRKGNAPYHWLYHKCSSCASYNTR 1252
Cdd:pfam14599    1 VDMEAYWRALDAEIAAQPMPEEYANWRVVILCNDCEAKSEVPFHFLGLKCSHCGSYNTR 59

Hemerythrin-like domain; Hemerythrin (Hr) like domains have the same four alpha helix bundle and a similar, but slightly different active site structure than hemerythrin. They are non-heme diiron binding proteins mainly found in bacteria and eukaryotes. Like Hr, they may be involved in oxygen transport or like human FBXL5 (F-box and leucine-rich repeat protein 5), a member of this group, play a role in cellular iron homeostasis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634  613 DLIFYFHKAMKKDLDYLVRGSARLATDY-SFLGEFQQRFHLIKFLYQIHSDAEDEIAFPALEAKGKLQNISQSYSIDHEL 691
Cdd:cd12108     1 DLLKLEHRAIRRELGRLARLAGALAAGGpDDARALAERFRFLATELHHHHTAEEELLFPALRERVPLAAVLDALEAEHAE 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634  692 EVEHLNKVSFLLNELAELNMLVLDhknvkyeklcmSLQDICKSIHKLLSEHLHREETELW 751
Cdd:cd12108    81 IDELLARLEALLPALLAGDAEDAE-----------ELAAALEALRTALREHLDEEEEELF 129

RING finger, H2 subclass, found in p53-induced RING-H2 protein (Pirh2) and similar proteins; Pirh2, also known as RING finger and CHY zinc finger domain-containing protein 1 (Rchy1), androgen receptor N-terminal-interacting protein, CH-rich-interacting match with PLAG1, RING finger protein 199 (RNF199), or zinc finger protein 363 (ZNF363), is a p53 inducible E3 ubiquitin-protein ligase that functions as a negative regulator of p53. It preferably ubiquitylates the tetrameric form of p53 in vitro and in vivo, suggesting a role of Pirh2 in downregulating the transcriptionally active form of p53 in the cell. Moreover, Pirh2 inhibits the transcriptional activity of p73, a homolog of the tumor suppressor p53, by promoting its ubiquitination. It also monoubiquitinates DNA polymerase eta (PolH) to suppress translesion DNA synthesis. Furthermore, Pirh2 functions as a negative regulator of the cyclin-dependent kinase inhibitor p27(Kip1) function by promoting ubiquitin-dependent proteasomal degradation. Pirh2 enhances androgen receptor (AR) signaling through inhibition of histone deacetylase 1 (HDAC1) and is overexpressed in prostate cancer. It interacts with TIP60 and this association may regulate Pirh2 stability. In addition, the oncoprotein pleomorphic adenoma gene like 2 (PLAGL2) can bind to the Pirh2 dimer and therefore control the stability of Pirh2. Pirh2 contains a total of nine zinc-binding sites with six located at the N-terminal region, two in the C3H2C3-type RING-H2 domain, and one in the C-terminal region. Nine zinc binding sites comprise three different zinc coordination schemes, including RING type cross-brace zinc coordination, C4 zinc finger, and a novel left-handed beta-spiral zinc-binding motif formed by three recurrent CCHC sequence motifs. This subfamily also includes Drosophila melanogaster Deltex, a ubiquitously expressed cytoplasmic ubiquitin E3 ligase that mediates Notch activation in Drosophila. It selectively suppresses T-cell activation through degradation of a key signaling molecule, MAP kinase kinase kinase 1 (MEKK1). It also inhibits Jun-mediated transcription at the stage of Ras-dependent Jun N-terminal protein kinase (JNK) activation. Deltex contains N-terminal two Notch-binding WWE domains that physically interact with the Notch ankyrin domains, a proline-rich motif that shares homology with SH3-binding domains, and a RING finger at the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 186478634 1147 NCPICHEYIFTSNSPVKALPCGHVMHSTCFQEYTCSH-YTCPICS 1190
Cdd:cd16464     1 NCPVCLEDLFTSREPVHVLPCGHLMHSTCFEEYLKSGnYRCPLCS 45

RING finger, H2 subclass, found in RING finger protein 115 (RNF115) and similar proteins; RNF115, also known as Rab7-interacting ring finger protein (Rabring 7), or zinc finger protein 364 (ZNF364), or breast cancer-associated gene 2 (BCA2), is an E3 ubiquitin-protein ligase that is an endogenous inhibitor of adenosine monophosphate-activated protein kinase (AMPK) activation and its inhibition increases the efficacy of metformin in breast cancer cells. It also functions as a co-factor in the restriction imposed by tetherin on HIV-1, and targets HIV-1 Gag for lysosomal degradation, impairing virus assembly and release, in a tetherin-independent manner. Moreover, RNF115 is a Rab7-binding protein that stimulates c-Myc degradation through mono-ubiquitination of MM-1. It also plays crucial roles as a Rab7 target protein in vesicle traffic to late endosome/lysosome and lysosome biogenesis. Furthermore, RNF115 and the related protein, RNF126 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. RNF115 contains an N-terminal BCA2 Zinc-finger domain (BZF), the AKT-phosphorylation sites, and the C-terminal C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 186478634 1148 CPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPICSKSL 1193
Cdd:cd16800     3 CPVCKED-YTVGEQVRQLPCNHFFHSDCIVPWLELHDTCPVCRKSL 47

RING finger, H2 subclass, found in the PA-TM-RING ubiquitin ligase family; The PA-TM-RING family represents a group of transmembrane-type E3 ubiquitin ligases, which has been characterized by an N-terminal transient signal peptide, a PA (protease-associated) domain, a TM (transmembrane) domain, as well as a C-terminal C3H2C3-type RING-H2 finger domain. It includes RNF13, RNF167, ZNRF4 (zinc and RING finger 4), GRAIL (gene related to anergy in lymphocytes)/RNF128, RNF130, RNF133, RNF148, RNF149 and RNF150 (which are more closely related), as well as RNF43 and ZNRF3, which have substantially longer C-terminal tail extensions compared with the others. PA-TM-RING proteins are expressed at low levels in all mammalian tissues and species, but they are not present in yeast. They play a common regulatory role in intracellular trafficking/sorting, suggesting that abrogation of their function may result in dysregulation of cellular signaling events in cancer.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 186478634 1148 CPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16454     2 CAICLEE-FKEGEKVRVLPCNHLFHKDCIDPWLEQHNTCPLC 42

RING finger, H2 subclass, found in RING finger protein 126 (RNF126) and similar proteins; RNF126 is a Bag6-dependent E3 ubiquitin ligase that is involved in the mislocalized protein (MLP) pathway of quality control. It regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). Moreover, RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation, and could be a novel therapeutic target in breast and prostate cancers. It is also able to ubiquitylate cytidine deaminase (AID), a poorly soluble protein that is essential for antibody diversification. In addition, RNF126 and the related protein, RNF115 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. RNF126 contains an N-terminal BCA2 Zinc-finger domain (BZF), the AKT-phosphorylation sites, and the C-terminal C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 186478634 1148 CPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPICSK 1191
Cdd:cd16801     2 CPVCKED-YTVGENVRQLPCNHLFHNDCIVPWLEQHDTCPVCRK 44

Hemerythrin domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634   52 HKAFRAQLAELQFLAgDTVRSGSDLAVE-LRSKFEFLKlVY--KYHSAAEDEVIFSAL---DTRVKNIVFNYSLEHDATD 125
Cdd:COG3945    11 HRNIRRLLAVLEKLL-DRLEEGEEVDFElLRDILDYIR-EFadRCHHPKEEDILFPRLeerGGEAAGPIAVLLAEHEQGR 88

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 186478634  126 DLFTSVFHWLN-VLEEEQGNRADVLREVVLCIGTIQssicQHMLKEERQVFPLMIENFSFEEQASL 190
Cdd:COG3945    89 QLTRELEEALEaYLAGDVVARDELAAALRAYIALLR----QHIAKEENVLFPLAERLLSDEDWEEL 150

RING finger, H2 subclass, found in RING finger protein 130 (RNF130) and similar proteins; RNF130, also known as Goliath homolog (H-Goliath), is a paralog of RNF128, also known as gene related to anergy in lymphocytes protein (GRAIL). It is a transmembrane E3 ubiquitin-protein ligase expressed in leukocytes. It has a self-ubiquitination property, and controls the development of T cell clonal anergy by ubiquitination. RNF130 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 186478634 1146 DNCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16803     1 DHCAVCIEG-YKQNDVVRILPCKHVFHKSCVDPWLNEHCTCPMC 43

RING finger, H2 subclass, found in synoviolin and similar proteins; Synoviolin, also known as synovial apoptosis inhibitor 1 (Syvn1), Hrd1, or Der3, is an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis and plays a role in homeostasis maintenance. It also targets tumor suppressor gene p53 for proteasomal degradation, suggesting crosstalk between ER associated degradation (ERAD) and p53 mediated apoptotic pathway under ER stress. Moreover, synoviolin controls body weight and mitochondrial biogenesis through negative regulation of the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1beta. It upregulates amyloid beta production by targeting a negative regulator of gamma-secretase, Retention in endoplasmic reticulum 1 (Rer1), for degradation. It is also involved in the degradation of endogenous immature nicastrin, and affects amyloid beta-protein generation. Moreover, synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of rheumatoid arthritis (RA). It functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of RA. It promotes inositol-requiring enzyme 1 (IRE1) ubiquitination and degradation in synovial fibroblasts with collagen-induced arthritis. Furthermore, the upregulation of synoviolin may represent a protective response against neurodegeneration in Parkinson's disease (PD). In addition, synoviolin is involved in liver fibrogenesis. Synoviolin contains a C3H2C2-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 186478634 1145 EDNCPICHEYIFTSNspvKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16479     1 DNTCIICREEMTVGA---KKLPCGHIFHLSCLRSWLQRQQTCPTC 42

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 186478634 1147 NCPICHEyifTSNSPVKaLPCGHVMHSTCFQEYTCSHYTCPICSKSLGD 1195
Cdd:cd16561     4 ECSICLE---DLNDPVK-LPCDHVFCEECIRQWLPGQMSCPLCRTELPD 48

RING finger, H2 subclass, found in RING finger proteins RNF111, RNF165, and similar proteins; The family includes RING finger proteins RNF111, RNF165, and similar proteins. RNF111, also known as Arkadia, is a nuclear E3 ubiquitin-protein ligase that targets intracellular effectors and modulators of transforming growth factor beta (TGF-beta)/Nodal-related signaling for polyubiquitination and proteasome-dependent degradation. It also interacts with the clathrin-adaptor 2 (AP2) complex and regulates endocytosis of certain cell surface receptors, leading to modulation of epidermal growth factor (EGF) and possibly other signaling pathways. The N-terminal half of RNF111 harbors three SUMO-interacting motifs (SIMs). It thus functions as a SUMO-targeted ubiquitin ligase (STUbL) that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response, as well as triggers degradation of signal-induced polysumoylated proteins, such as the promyelocytic leukemia protein (PML). RNF165, also known as Arkadia-like 2, Arkadia2, or Ark2C, is an E3 ubiquitin ligase with homology to the C-terminal half of RNF111. It is expressed specifically in the nervous system, and can serve to amplify neuronal responses to specific signals. It acts as a positive regulator of bone morphogenetic protein (BMP)-Smad signaling that is involved in motor neuron (MN) axon elongation. Both RNF165 and RNF111 contain a C-terminal C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 186478634 1146 DNCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16474     1 EKCTICLSD-FEEGEDVRRLPCMHLFHQECVDQWLSTNKRCPIC 43

zinc-RING finger domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 186478634  1147 NCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCShYTCPICSK 1191
Cdd:pfam14634    1 HCNKCFKE-LSKTRPFYLTSCGHIFCEECLTRLLQE-RQCPICKK 43

RING finger, H2 subclass, found in DAZ (deleted in azoospermia)-interacting protein 3 (DZIP3) and similar proteins; DZIP3, also known as RNA-binding ubiquitin ligase of 138 kDa (RUL138) or 2A-HUB protein, is an RNA-binding E3 ubiquitin-protein ligase that interacts with coactivator-associated arginine methyltransferase 1 (CARM1) and acts as a transcriptional coactivator of estrogen receptor (ER) alpha. It is also a histone H2A ubiquitin ligase that catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatorial component of the repression machinery required for repressing a specific chemokine gene expression program, critically modulating migratory responses to Toll-like receptors (TLR) activation. DZIP3 contains a C3H2C3-type RING-H2 finger at the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 186478634 1148 CPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16460     3 CVICHEA-FSDGDRLLVLPCAHKFHTQCIGPWLDGQQTCPTC 43

RING finger, H2 subclass, found in RING finger protein 150 (RNF150) and similar proteins; RNF150 is a RING finger protein and its polymorphisms may be associated with chronic obstructive pulmonary disease (COPD) risk in the Chinese population. Further studies with larger numbers of participants worldwide are needed for validation of the relationships between RNF150 genetic variants and the pathogenesis of COPD. RNF150 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 186478634 1146 DNCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPICSKSL 1193
Cdd:cd16805     7 DNCAVCIEG-YKPNDVVRILPCRHLFHKSCVDPWLLDHRTCPMCKMNI 53

RING finger, H2 subclass, found in RING finger proteins, RNF130, RNF149, RNF150 and similar proteins; This subfamily includes RING finger proteins, RNF130, RNF149 and RNF150, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence. RNF130, also known as Goliath homolog (H-Goliath), is a paralog of RNF128. It is a transmembrane E3 ubiquitin-protein ligase expressed in leukocytes. It has a self-ubiquitination property and controls the development of T cell clonal anergy by ubiquitination. RNF133 is a testis-specific endoplasmic reticulum-associated E3 ubiquitin ligase that may play a role in sperm maturation through an ER-associated degradation (ERAD) pathway. RNF149, also known as DNA polymerase-transactivated protein 2, is an E3 ubiquitin-protein ligase that induces the ubiquitination of wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and promotes its proteasome-dependent degradation. RNF150 polymorphisms may be associated with chronic obstructive pulmonary disease (COPD) risk in the Chinese population. This subfamily also includes Drosophila melanogaster protein goliath (d-goliath), also known as protein g1, which is one of the founding members of the group. It was originally identified as a transcription factor involved in the embryo mesoderm formation.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 186478634 1147 NCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16668     1 CCAVCIEP-YKPSDVIRILPCKHIFHKSCVDPWLLEHRTCPMC 42

Hemerythrin-like domain of FBXL5-like proteins; Human FBXL5 (F-box and leucine-rich repeat protein 5) protein plays a role in cellular iron homeostasis. It is part of an E3 ubiquitin ligase complex that targets the iron regulatory protein IRP2 for proteasomal degradation. The FBXL5's stability is regulated by iron concentration, with its iron- and oxygen-binding hemerythrin domain acting as a ligand-dependent regulatory switch.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634  615 IFYF-HKAMKKDL-DYLVRGSArlaTDYSFLGEFQQ---RFHLIKFLYQIHSDAEDEIAFPALEAKGKlqnisQSYSIDH 689
Cdd:cd12109     4 VYGFiHKALRALLfDLLQKLGR---TDFSDPQDLAAlleSLRRLLQEFKAHEQHENEFIHPLLEKRLP-----GLSAAVA 75

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 186478634  690 ELEVEHlnkvsfllnELAElnMLVLDHKNVKYEKLCMSLQDICKSIHKLLSE-------HLHREETE----LWCLFRD 756
Cdd:cd12109    76 NEHSDH---------DLSI--MLLLELLGALRTAPEAERPAAGRQLYRALAAfvadnlpHMHEEETVfqplLWEYFSD 142

RING finger, H2 subclass, found in RING finger protein 111 (RNF111) and similar proteins; RNF111, also known as Arkadia, is a nuclear E3 ubiquitin-protein ligase that targets intracellular effectors and modulators of transforming growth factor beta (TGF-beta)/Nodal-related signaling for polyubiquitination and proteasome-dependent degradation. It acts as an amplifier of Nodal signals, and enhances the dorsalizing activity of limiting amounts of Xnr1, a Nodal homolog, and requires Nodal signaling for its function. The loss of RNF111 results in early embryonic lethality, with defects attributed to compromised Nodal signaling. RNF111 also regulates tumor metastasis by modulation of the TGF-beta pathway. Its ubiquitination can be modulated by the four and a half LIM-only protein 2 (FHL2) that activates TGF-beta signal transduction. Furthermore, RNF111 interacts with the clathrin-adaptor 2 (AP2) complex and regulates endocytosis of certain cell surface receptors, leading to modulation of epidermal growth factor (EGF) and possibly other signaling pathways. In addition, RNF111 has been identified as a small ubiquitin-like modifier (SUMO)-binding protein with clustered SUMO-interacting motifs (SIMs) that together form a SUMO-binding domain (SBD). It thus functions as a SUMO-targeted ubiquitin ligase (STUbL) that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response, as well as triggers degradation of signal-induced polysumoylated proteins, such as the promyelocytic leukemia protein (PML). The N-terminal half of RNF111 harbors three SIMs. Its C-terminal half show high sequence similarity with RING finger protein 165 (RNF165), where it contains two serine rich domains, two nuclear localization signals, an NRG-TIER domain, and a C-terminal C3H2C3-type RING-H2 finger that is required for polyubiqutination and proteasome-dependent degradation of phosphorylated forms of Smad2/3 and three major negative regulators of TGF-beta signaling, Smad7, SnoN and c-Ski.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 186478634 1141 EKCLEDNCPICHEyIFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16681     6 EEDTEEKCTICLS-ILEEGEDVRRLPCMHLFHQVCVDQWLITNKKCPIC 53

RING finger, H2 subclass, found in Arabidopsis thaliana RING-type E3 ubiquitin transferase BIG BROTHER (BB) and similar proteins; BB (also known as protein ENHANCER OF DA1-1 or EOD1) is an E3 ubiquitin-protein ligase that limits organ size, and possibly seed size, in a dose-dependent manner. It negatively regulates the duration of cell proliferation in leaves and petals independently of the major phytohormones (e.g. auxin, cytokinin, gibberellin, brassinosteroids, ethylene, abscisic acid, jasmonic acid), probably by targeting growth stimulators for degradation. It limits the proliferation of root meristematic cells. BB polyubiquitinates DA1. It is involved in the promotion of leaf senescence, in addition to its function in restricting plant growth. BB-related is an E3 ubiquitin-ligase probably involved in organ size regulation. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 186478634 1145 EDNCPIC-HEYifTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPICSKS 1192
Cdd:cd23115     4 NERCVICrLEY--EEGEDLLTLPCKHCYHSECIQQWLQINKVCPVCSAE 50

first RING finger, H2 subclass, found in RING finger protein 32 (RNF32) and similar proteins; RNF32 is mainly expressed in testis spermatogenesis, most likely in spermatocytes and/or in spermatids, suggesting a possible role in sperm formation. RNF32 contains two C3H2C3-type RING-H2 fingers separated by an IQ domain of unknown function. Although the biological function of RNF32 remains unclear, proteins with double RING-H2 fingers may act as scaffolds for binding several proteins that function in the same pathway. This model corresponds to the first RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 186478634 1148 CPICHEyIFTSNSPVkALPCGHVMHSTCFQ--EYTCSHYTCPICSKS 1192
Cdd:cd16677     2 CPICLE-DFGLQQQV-LLSCSHVFHRACLEsfERFSGKKTCPMCRKE 46

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 186478634 1148 CPICHEYIFTS---------NSPVKALPCGHVMHSTCFQEYTCSHYTCPICSKSL-GDMQ 1197
Cdd:COG5243   290 CTICMDEMFHPdheplprglDMTPKRLPCGHILHLHCLKNWLERQQTCPICRRPViFDQS 349

RING finger, HC subclass, found in RING finger protein 138 (RNF138) and similar proteins; RNF138, also known as Nemo-like kinase-associated RING finger protein (NARF) or NLK-associated RING finger protein, is an E3 ubiquitin-protein ligase that plays an important role in glioma cell proliferation, apoptosis, and cell cycle. It specifically cooperates with the E2 conjugating enzyme E2-25K (Hip-2/UbcH1), regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF), and further suppresses Wnt-beta-catenin signaling. RNF138, together with three closely related proteins: RNF114, RNF125 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 186478634 1148 CPICHEyIFTSnsPVKALPCGHVMHSTCFQE-YTCSHYTCPICSKSLG 1194
Cdd:cd16544     5 CPVCQE-VLKD--PVELPPCRHIFCKACILLaLRSSGARCPLCRGPVG 49

RING finger, H2 subclass, found in RING finger protein 128 (RNF128) and similar proteins; This subfamily includes RING finger proteins RNF128, RNF133, RNF148, and similar proteins, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger followed by a putative PEST sequence. RNF128, also known as gene related to anergy in lymphocytes protein (GRAIL), is a type 1 transmembrane E3 ubiquitin-protein ligase that is a critical regulator of adaptive immunity and development. It inhibits cytokine gene transcription, is expressed in anergic CD4+ T cells, and has been implicated in primary T cell activation, survival, and differentiation, as well as in T cell anergy and oral tolerance. It induces T cell anergy through the ubiquitination activity of its cytosolic RING finger. It regulates expression of the costimulatory molecule CD40L on CD4 T cells, and ubiquitinates the costimulatory molecule CD40 ligand (CD40L) during the induction of T cell anergy. Moreover, RNF128 interacts with the luminal/extracellular portion of both CD151 and the related tetraspanin CD81 via its PA domain, which promoted ubiquitination of cytosolic lysine residues. It also down-modulates the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. Furthermore, Rho guanine dissociation inhibitor (RhoGDI) has been identified as a potential substrate of RNF128, suggesting a role for Rho effector molecules in T cell anergy. In addition, RNF128 plays a role in environmental stress responses. It promotes environmental salinity tolerance in euryhaline tilapia. RNF133 is a testis-specific endoplasmic reticulum-associated E3 ubiquitin ligase that is mainly present in the cytoplasm of elongated spermatids. It may play a role in sperm maturation through an ER-associated degradation (ERAD) pathway. RNF148 is a testis-specific E3 ubiquitin ligase that is abundantly expressed in testes and slightly expressed in pancreas. Its expression is regulated by histone deacetylases.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 186478634 1146 DNCPICHEyIFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16802     1 DSCAVCIE-PYKPNDVVRILTCNHLFHKNCIDPWLLEHRTCPMC 43

RING finger, H2 subclass, found in Arabidopsis thaliana protein ABA INSENSITIVE RING PROTEIN 1 (AIRP1) and similar proteins; This subfamily includes Arabidopsis thaliana AIRP1 and RING-H2 finger B1a (RHB1A). AIRP1, also known as RING-type E3 ubiquitin transferase AIRP1, possesses E3 ubiquitin-protein ligase activity in vitro when associated with the E2 enzyme UBC8. It plays combinatory roles with AIRP2 in the positive regulation of the abscisic acid-mediated drought stress response. RHB1A is a probable E3 ubiquitin-protein ligase. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 186478634 1145 EDNCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPICSKSL 1193
Cdd:cd23116     2 EDVCPTCLEG-YTEENPKLLTKCGHHFHLACIYEWMERSERCPVCDKEM 49

RING finger, H2 subclass, found in RING finger protein 215 (RNF215) and similar proteins; This family includes uncharacterized protein RNF215 and similar proteins. Although its biological function remains unclear, RNF215 shares high sequence similarity with PA-TM-RING ubiquitin ligases, which have been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 186478634 1146 DNCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPICSKSL 1193
Cdd:cd16670     1 ESCAVCLDQ-FYKNQCLRVLPCLHEFHRDCVDPWLLLQQTCPLCKRNI 47

RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins; This subfamily includes RING finger proteins RNF38, RNF44, and similar proteins. RNF38 is a nuclear E3 ubiquitin protein ligase that plays a role in regulating p53. RNF44 is an uncharacterized RING finger protein that shows high sequence similarity to RNF38. Both RNF38 and RNF44 contain a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), and a C3H2C3-type RING-H2 finger. In addition, RNF38 harbors two potential nuclear localization signals.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 186478634 1145 EDNCPICHeYIFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16472     2 QTQCVVCM-CDYEKRQLLRVLPCSHEFHAKCIDKWLKTNRTCPIC 45

Zinc finger, C3HC4 type (RING finger);

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 186478634  1148 CPICHEYIFTsnsPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:pfam13923    2 CPICMDMLKD---PSTTTPCGHVFCQDCILRALEASNECPLC 40

RING finger, H2 subclass, found in Arabidopsis thaliana protein SUGAR INSENSITIVE 3 (SIS3) and similar proteins; SIS3 is an E3 ubiquitin-protein ligase that acts as a positive regulator of sugar signaling during early seedling development. SIS3 contains a C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 186478634 1146 DNCPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd23118     1 KTCTICLED-FEDGEKLRVLPCQHQFHSECVDQWLRRNPKCPVC 43

RING finger, H2 subclass, found in RING finger protein 165 (RNF165) and similar proteins; RNF165, also known as Arkadia-like 2, Arkadia2, or Ark2C, is an E3 ubiquitin ligase with homology to the C-terminal half of RNF111. It is expressed specifically in the nervous system, and can serve to amplify neuronal responses to specific signals. It acts as a positive regulator of bone morphogenetic protein (BMP)-Smad signaling that is involved in motor neuron (MN) axon elongation. RNF165 contains two serine rich domains, a nuclear localization signal, an NRG-TIER domain, and a C-terminal C3H2C3-type RING-H2 finger that is responsible for the enhancement of BMP-Smad1/5/8 signaling in the spinal cord.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 186478634 1141 EKCLEDNCPICHEyIFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16682     3 ESDTDEKCTICLS-MLEDGEDVRRLPCMHLFHQLCVDQWLAMSKKCPIC 50

RING finger, H2 subclass, found in RING finger protein 139 (RNF139) and similar proteins; RNF139, also known as translocation in renal carcinoma on chromosome 8 protein (TRC8), is an endoplasmic reticulum (ER)-resident multi-transmembrane protein that functions as a potent growth suppressor in mammalian cells, inducing G2/M arrest, decreased DNA synthesis and increased apoptosis. It is a tumor suppressor that has been implicated in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control. A mutation in RNF139 has been identified in families with hereditary renal (RCC) and thyroid cancers. RNF139 physically and functionally interacts with von Hippel-Lindau (VHL), which is part of an SCF related E3-ubiquitin ligase complex with "gatekeeper" function in renal carcinoma and is defective in most sporadic clear-cell renal cell carcinomas (ccRCC). It suppresses growth and functions with VHL in a common pathway. RNF139 also suppresses tumorigenesis by targeting heme oxygenase-1 for ubiquitination and degradation. Moreover, RNF139 is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells, suggesting a role of RNF139 in dysgerminoma. In addition, RNF139 forms an integral part of a novel multi-protein ER complex, containing MHC I, US2, and signal peptide peptidase, which is associated with the ER-associated degradation (ERAD) pathway. It is required for the ubiquitination of MHC class I molecules before dislocation from the ER. As a novel sterol-sensing ER membrane protein, RNF139 hinders sterol regulatory element-binding protein-2 (SREBP-2) processing through interaction with SREBP-2 and SREBP cleavage-activated protein (SCAP), regulating its own turnover rate via its E3 ubiquitin ligase activity. RNF139 shows two regions of similarity with the receptor for sonic hedgehog (SHH), Patched. The first region corresponds to the second extracellular domain of Patched, which is involved in binding SHH. The second region is a putative sterol-sensing domain (SSD). The C-terminal half of RNF139 contains a C3H2C3-type RING-H2 finger with E3-ubiquitin ligase activity in vitro.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 186478634 1144 LEDNCPICHEYIFTSnspVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16683     3 IDDVCAICYQEFTTS---ARITPCNHYFHALCLRKWLYIQDTCPMC 45

RING finger, H2 subclass, found in BRCA1-associated protein (BRAP2) and similar proteins; BRAP2, also known as impedes mitogenic signal propagation (IMP), RING finger protein 52, or renal carcinoma antigen NY-REN-63, is a novel cytoplasmic protein interacting with the two functional nuclear localization signal (NLS) motifs of BRCA1, a nuclear protein linked to breast cancer. It also binds to the SV40 large T antigen NLS motif and the bipartite NLS motif found in mitosin. BRAP2 serves as a cytoplasmic retention protein and plays a role in the regulation of nuclear protein transport. It contains an N-terminal RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), followed by a C3H2C3-type RING-H2 finger and a UBP-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 186478634 1147 NCPICHEYIFTSNSPVKALPCGHVMHSTCFQEYTCShyTCPIC 1189
Cdd:cd16457     2 TCPVCLERMDESVSGILTILCNHSFHCSCLSKWGDS--SCPVC 42

RING finger, HC subclass, found in seven in absentia homolog 2 (SIAH2) and similar proteins; SIAH2 is an E3 ubiquitin-protein ligase that contributes to proteasome-mediated degradation of multiple targets in numerous cellular processes. It targets the ubiquitylation and degradation of tumor necrosis factor receptor-associated factor 2 (TRAF2) under stress conditions, which is required for the cell to commit to undergoing apoptosis. It is, therefore, a key regulator of TRAF2-dependent signaling in response to tumor necrosis factor-alpha (TNF-alpha) treatment and UV irradiation. SIAH2 modulates the polyubiquitination of G protein pathway suppressor 2 (GPS2), and targets it for proteasomal degradation. It is also a regulator of NF-E2-related factor 2 (Nrf2), a key regulator of cellular oxidative response, and contributes to the degradation of Nrf2 irrespective of its phosphorylation status. Moreover, SIAH2 contributes to castration-resistant prostate cancer (CRPC) by regulation of androgen receptor (AR) transcriptional activity. It enhances AR transcriptional activity and prostate cancer cell growth. Its stability can be regulated by AKR1C3. SIAH2 also inhibits tyrosine kinase-2 (TYK2)-STAT3 signaling in lung carcinoma cells. Furthermore, SIAH2 regulates obesity-induced adipose tissue inflammation by altering peroxisome proliferator-activated receptor gamma (PPAR gamma) protein levels and selectively regulating PPAR gamma activity. It also functions as a regulator of the nuclear hormone receptor RevErbalpha (Nr1d1) stability and rhythmicity, and overall circadian oscillator function. In addition, SIAH2 is an essential component of the hypoxia response Hippo signaling pathway and has been implicated in normal development and tumorigenesis. It modulates the hypoxia pathway upstream of hypoxia-induced transcription factor subunit HIF-1alpha, and therefore may play an important role in angiogenesis in response to hypoxic stress in endothelial cells. It also stimulates transcriptional coactivator YAP1 by destabilizing serine/threonine-protein kinase LATS2, a critical component of the Hippo pathway, in response to hypoxia. Meanwhile, SIAH2 is involved in regulation of tight junction integrity and cell polarity under hypoxia, through its regulation of apoptosis-stimulating proteins of p53 subunit 2 (ASPP2) stability. SIAH2 contains an N-terminal C3HC4-type RING-HC finger, two zinc-finger subdomains, and a C-terminal tumor necrosis factor (TNF) receptor associated factor (TRAF)-like substrate-binding domain (SBD) responsible for dimer formation.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 186478634 1148 CPICHEYIFtsnSPVKALPCGHVMHSTCFQEYTCshytCPICSKSLGD 1195
Cdd:cd16752     6 CPVCFDYVL---PPILQCQAGHLVCNQCRQKLSC----CPTCRGPLTP 46

RING finger, H2 subclass, found in RING finger proteins RNF43, ZNRF3, and similar proteins; RNF43 and ZNRF3 (also known as RNF203) are transmembrane E3 ubiquitin-protein ligases that belong to the PA-TM-RING ubiquitin ligase family, characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger followed by a long C-terminal region. Both RNF43 and RNF203 function as tumor suppressors involved in the regulation of Wnt/beta-catenin signaling. They negatively regulate Wnt signaling by interacting with complexes of frizzled (FZD) receptors and low-density lipoprotein receptor-related protein (LRP) 5/6, which leads to ubiquitination of FZD and endocytosis of the Wnt receptor. Dishevelled (DVL), a positive Wnt regulator, is required for ZNRF3/RNF43-mediated ubiquitination and degradation of FZD. They also associate with R-spondin 1 (RSPO1). This interaction may block FZD ubiquitination and enhances Wnt signaling.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 186478634 1148 CPICHEyIFTSNSPVKALPCGHVMHSTCFQEYTCSHYTCPIC 1189
Cdd:cd16666     2 CAICLE-EYEEGQELRVLPCQHEFHRKCVDPWLLQNHTCPLC 42

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 186478634 1148 CPICHEYiFTSNSPVKALPCGHVMHSTCFQEYTCSH-YTCPICSKSL 1193
Cdd:COG5540   326 CAICMSN-FIKNDRLRVLPCDHRFHVGCVDKWLLGYsNKCPVCRTAI 371