RING finger, HC subclass, found in RING finger and SPRY domain-containing protein 1 (RSPRY1) and similar proteins; RSPRY1 is a hypothetical RING and SPRY domain-containing protein of unknown physiological function. Mutations in its corresponding gene RSPRY1 may associate with a distinct skeletal dysplasia syndrome. RSPRY1 contains a B30.2/SPRY domain and a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1315370143 523 RENCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRKEI 565
Cdd:cd16566     1 REDSCTLCFDKVADTELRPCGHSGFCMECALQLETCPLCRQPI 43

Domain in SPla and the RYanodine Receptor; Domain of unknown function. Distant homologues are domains in butyrophilin/marenostrin/pyrin homologues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143  359 GVWYYEVTVVTSGVMQIGWATRDSKFlnHEGYGIGDDEYSCAYDGCRQLIWYNARSKPHVHPCWKEGDTVGFLLDLNEKQ 438
Cdd:smart00449   2 GRHYFEVEIGDGGHWRVGVATKSVPR--GYFALLGEDKGSWGYDGDGGKKYHNSTGPEYGLPLQEPGDVIGCFLDLEAGT 79

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 1315370143  439 MIFFLNGNQLpPEKQVFSSTVSG-FFAAASFMSYQQCEFNFG 479
Cdd:smart00449  80 ISFYKNGKYL-HGLAFFDVKFSGpLYPAFSLGSGNSVRLNFG 120

RING finger, HC subclass, found in RING finger and SPRY domain-containing protein 1 (RSPRY1) and similar proteins; RSPRY1 is a hypothetical RING and SPRY domain-containing protein of unknown physiological function. Mutations in its corresponding gene RSPRY1 may associate with a distinct skeletal dysplasia syndrome. RSPRY1 contains a B30.2/SPRY domain and a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1315370143 523 RENCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRKEI 565
Cdd:cd16566     1 REDSCTLCFDKVADTELRPCGHSGFCMECALQLETCPLCRQPI 43

SPRY domain; SPRY domains, first identified in the SP1A kinase of Dictyostelium and rabbit Ryanodine receptor (hence the name), are homologous to B30.2. SPRY domains have been identified in at least 11 protein families, covering a wide range of functions, including regulation of cytokine signaling (SOCS), RNA metabolism (DDX1 and hnRNP), immunity to retroviruses (TRIM5alpha), intracellular calcium release (ryanodine receptors or RyR) and regulatory and developmental processes (HERC1 and Ash2L). B30.2 also contains residues in the N-terminus that form a distinct PRY domain structure; i.e. B30.2 domain consists of PRY and SPRY subdomains. B30.2 domains comprise the C-terminus of three protein families: BTNs (receptor glycoproteins of immunoglobulin superfamily); several TRIM proteins (composed of RING/B-box/coiled-coil or RBCC core); Stonutoxin (secreted poisonous protein of the stonefish Synanceia horrida). TRIM/RBCC proteins are involved in a variety of processes, including apoptosis, cell cycle regulation, cell growth, senescence, viral response, meiosis, cell differentiation, and vesicular transport. Genes belonging to this family are implicated in several human diseases that vary from cancer to rare genetic syndromes. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site. While SPRY domains are evolutionarily ancient, B30.2 domains are a more recent adaptation where the SPRY/PRY combination is a possible component of immune defense. Mutations found in the SPRY-containing proteins have shown to cause Mediterranean fever and Opitz syndrome.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 359 GVWYYEVTVVT--SGVMQIGWATRDSKFLNHEGYGigDDEYSCAYDGCRQLIWYNARSKPHVHPcWKEGDTVGFLLDLNE 436
Cdd:cd11709     1 GKWYWEVRVDSgnGGLIQVGWATKSFSLDGEGGVG--DDEESWGYDGSRLRKGHGGSSGPGGRP-WKSGDVVGCLLDLDE 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1315370143 437 KQMIFFLNGNQLPPEKQVFSSTVSGFFAAASFMSYQQCEFN 477
Cdd:cd11709    78 GTLSFSLNGKDLGVAFTNLFLKGGGLYPAVSLGSGQGVTIN 118

Domain in SPla and the RYanodine Receptor; Domain of unknown function. Distant homologues are domains in butyrophilin/marenostrin/pyrin homologues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143  359 GVWYYEVTVVTSGVMQIGWATRDSKFlnHEGYGIGDDEYSCAYDGCRQLIWYNARSKPHVHPCWKEGDTVGFLLDLNEKQ 438
Cdd:smart00449   2 GRHYFEVEIGDGGHWRVGVATKSVPR--GYFALLGEDKGSWGYDGDGGKKYHNSTGPEYGLPLQEPGDVIGCFLDLEAGT 79

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 1315370143  439 MIFFLNGNQLpPEKQVFSSTVSG-FFAAASFMSYQQCEFNFG 479
Cdd:smart00449  80 ISFYKNGKYL-HGLAFFDVKFSGpLYPAFSLGSGNSVRLNFG 120

RING finger, HC subclass, found in RING finger and SPRY domain-containing protein 1 (RSPRY1) and similar proteins; RSPRY1 is a hypothetical RING and SPRY domain-containing protein of unknown physiological function. Mutations in its corresponding gene RSPRY1 may associate with a distinct skeletal dysplasia syndrome. RSPRY1 contains a B30.2/SPRY domain and a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1315370143 523 RENCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRKEI 565
Cdd:cd16566     1 REDSCTLCFDKVADTELRPCGHSGFCMECALQLETCPLCRQPI 43

SPRY domain in Ash2; This SPRY domain is found at the C-terminus of Ash2 (absent, small, or homeotic discs 2) -like proteins, core components of all mixed-lineage leukemia (MLL) family histone methyltransferases. Ash2 is a member of the trithorax group of transcriptional regulators of the Hox genes. Recent studies show that the SPRY domain of Ash2 mediates the interaction with RbBP5 and has an important role in regulating the methyltransferase activity of MLL complexes. In yeast, Ash2 is involved in histone methylation and is required for the earliest stages of embryogenesis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 331 LKISPHGLEARCDaSSFESVRCTFCVDTGVWYYEVTVVTSGVMQ-----IGWATRDSKFlnheGYGIGDDEYSCAY---D 402
Cdd:cd12872     1 LKLSEDRLTVTGE-KGYRMARANHGVREGKWYFEVKILEGGGTEtghvrVGWSRREASL----QAPVGYDKYSYAIrdkD 75

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 403 GCrqlIWYNARSKPHVHPCWKEGDTVGFLLDLNEkqMIFFLNG-NQ------LPPEKqvfsstvsGFFAAAS-FMSyQQC 474
Cdd:cd12872    76 GS---KFHQSRGKPYGEPGFKEGDVIGFLITLPK--IEFFKNGkSQgvafedIYGTG--------GYYPAVSlYKG-ATV 141

                  ....*
gi 1315370143 475 EFNFG 479
Cdd:cd12872   142 TINFG 146

SPRY domain 1 (SPRY1) of ryanodine receptor (RyR); This SPRY domain is the first of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, but no specific function has been found for this first SPRY domain of the RyRs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 361 WYYEVTV--VTSGVMQ-----IGWAT---RDSKFLNHEGYG---IGDDEYSCAYDGCRqlIWYNARSK---PHVHPCWKE 424
Cdd:cd12877    20 WYFEVEVdhVEQFTHQpahlrVGWANtsgYVPYPGGGEGWGgngVGDDLYSYGFDGLH--LWTGGRSRrvtSGTQHLLKK 97

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1315370143 425 GDTVGFLLDLNEKQMIFFLNGNQLPPEKQVFSSTVsGFFAAASFMSYQQCEFNFG 479
Cdd:cd12877    98 GDVVGCCLDLSVPSISFRVNGRPVQGMFENFNLDG-MFFPVMSFSAGVSCRFLLG 151

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein NEURL1A, NEURL1B, and similar proteins; This subfamily includes Drosophila neuralized (D-neu) protein, and its two mammalian homologs, NEURL1A and NEURL1B. D-neu is a regulator of the developmentally important Notch signaling pathway. NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of D-neu. It functions as an E3 ubiquitin-protein ligase that directly interacts with and monoubiquitinates cytoplasmic polyadenylation element-binding protein 3 (CPEB3), an RNA binding protein and a translational regulator of local protein synthesis, which facilitates hippocampal plasticity and hippocampal-dependent memory storage. It also acts as a potential tumor suppressor that causes apoptosis and downregulates Notch target genes in medulloblastoma. NEURL1B, also known as neuralized-2 (NEUR2) or neuralized-like protein 3, is another mammalian homolog of D-neu protein. It functions as an E3 ubiquitin-protein ligase that interacts with and ubiquitinates Delta. Thus, it plays a role in the endocytic pathways for Notch signaling by working cooperatively with another E3 ligase, Mind bomb-1 (Mib1), in Delta endocytosis to hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-positive vesicles. Members of this subfamily contain two neuralized homology regions (NHRs) responsible for Neural-ligand interactions and a modified C3HC5-type RING-HC finger required for ubiquitin ligase activity. The C3HC5-type RING-HC finger is distinguished from typical C3HC4-type RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQL----ETCPLCRKEIVSRIR 570
Cdd:cd16647     4 CVICYERPVDTVLYRCGHMCMCYDCALQLkrrgGSCPICRAPIKDVIK 51

SPRY domain in Ran binding proteins, SSH4, HECT E3 and SPRYD3; This family includes SPRY domains found in Ran binding proteins (RBP or RanBPM) 9 and 10, SSH4 (suppressor of SHR3 null mutation protein 4), SPRY domain-containing protein 3 (SPRYD3) as well as HECT, a C-terminal catalytic domain of a subclass of ubiquitin-protein ligase (E3). RanBP9 and RanBP10 act as androgen receptor (AR) coactivators. Both consist of the N-terminal proline- and glutamine-rich regions, the SPRY domain, and LisH-CTLH and CRA motifs. The SPRY domain in SSH4 may be involved in cargo recognition, either directly or by combination with other adaptors, possibly leading to a higher selectivity. SPRYD3 is highly expressed in most tissues in humans, possibly involved in important cellular processes. HECT E3 mediates the direct transfer of ubiquitin from E2 to substrate.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 356 VDTGVWYYEVTVV---TSGVMQIGWATRDSKFLNHegygIGDDEYSCAY---DGCrqlIWYNARSKPHVHPCWKEGDTVG 429
Cdd:cd12885    11 PKVPVFYFEVTILdlgEKGIVSIGFCTSGFPLNRM----PGWEDGSYGYhgdDGR---VYLGGGEGENYGPPFGTGDVVG 83

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1315370143 430 FLLDLNEKQMIFFLNGNQLPPekqVFSSTVSG-FFAAASFmSYQQCEF--NFG 479
Cdd:cd12885    84 CGINFKTGEVFFTKNGELLGT---AFENVVKGrLYPTVGL-GSPGVKVrvNFG 132

RING finger, HC subclass, found in inhibitor of apoptosis proteins (IAPs); IAPs are frequently overexpressed in cancer and associated with tumor cell survival, chemoresistance, disease progression, and poor prognosis. They function primarily as negative regulators of cell death. They regulate caspases and apoptosis through the inhibition of specific members of the caspase family of cysteine proteases. In addition, IAPs has been implicated in a multitude of other cellular processes, including inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis. IAPs in this family includes cellular inhibitor of apoptosis protein c-IAP1 (BIRC2) and c-IAP2 (BIRC3), XIAP (BIRC4), BIRC7, and BIRC8, all of which contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. The UBA domain is only absent in mammalian homologs of BIRC7. Moreover, c-IAPs contains an additional caspase activation and recruitment domain (CARD) between the UBA and C3HC4-type RING-HC domains. The CARD domain may serve as a protein interaction surface.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1315370143 524 ENCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRK 563
Cdd:cd16510     1 EKLCKICMDREVNIVFLPCGHLVTCAQCAASLRKCPICRT 40

RING finger, HC subclass, found in apoptosis protein c-IAP1, c-IAP2, livin, and similar proteins; The cellular inhibitor of apoptosis protein c-IAPs function as ubiquitin E3 ligases that mediate the ubiquitination of substrates involved in apoptosis, nuclear factor-kappaB (NF-kappaB) signaling, and oncogenesis. Unlike other IAPs, such as XIAP, c-IAPs exhibit minimal binding to caspases and may not play an important role in the inhibition of these proteases. c-IAP1, also known as baculoviral IAP repeat-containing protein BIRC2, IAP-2, RING finger protein 48, or TNFR2-TRAF-signaling complex protein 2, is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. It can also regulate E2F1 transcription factor-mediated control of cyclin transcription in the nucleus. c-IAP2, also known as BIRC3, IAP-1, apoptosis inhibitor 2 (API2), or IAP homolog C, also influences ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-kappaB. c-IAPs contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), a caspase activation and recruitment domain (CARD) that serves as a protein interaction surface, and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. Livin, also known as baculoviral IAP repeat-containing protein 7 (BIRC7), kidney inhibitor of apoptosis protein (KIAP), melanoma inhibitor of apoptosis protein (ML-IAP), or RING finger protein 50, was identified as the melanoma IAP. It plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is regulated by the inhibition of caspase-3, -7, and -9. Its E3 ubiquitin-ligase-like activity promotes degradation of Smac/DIABLO, a critical endogenous regulator of all IAPs. Unlike other family members, mammalian livin contains a single BIR domain and a C3HC4-type RING-HC finger. The UBA domain can be detected in non-mammalian homologs of livin.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1315370143 524 ENCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRKEIVSRIR 570
Cdd:cd16713     7 ERTCKVCMDKEVSIVFIPCGHLVVCTECAPSLRKCPICRATIKGTVR 53

RING finger, HC subclass, found in neuralized-like protein 3 (NEURL3) and similar proteins; NEURL3, also known as lung-inducible neuralized-related C3HC4 RING domain protein (LINCR), is a novel inflammation-induced E3 ubiquitin-protein ligase encoded by LINCR, a glucocorticoid-attenuated response gene induced in the lung during endotoxemia. It is expressed in alveolar epithelial type II cells, preferentially interacts with the ubiquitin-conjugating enzyme UbcH6, and generates polyubiquitin chains linked via non-canonical lysine residues. Overexpression of NEURL3 in the developing lung epithelium inhibits distal differentiation and induces cystic changes in the Notch signaling pathway. NEURL3 contains an N-terminal neuralized homology repeat (NHR) domain similar to the SPRY (SPla and the RYanodine receptor) domain and a C-terminal C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQL----ETCPLCRKEI 565
Cdd:cd16552     4 CAICFHHTANTRLVPCGHSHFCGSCAWHIfrdtARCPVCRWQI 46

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein 1 (CARP1) and similar proteins; CARP1, also known as caspase regulator CARP1, FYVE-RING finger protein Momo, RING finger homologous to inhibitor of apoptosis protein (RFI), RING finger protein 34 (RNF34), or RING finger protein RIFF, is a nuclear protein that functions as a specific E3 ubiquitin ligase for the transcriptional coactivator PGC-1alpha, a master regulator of energy metabolism and adaptive thermogenesis in the brown fat cell which negatively regulates brown fat cell metabolism. It is preferentially expressed in esophageal, gastric, and colorectal cancers, suggesting a possible association with the development of digestive tract cancers. It regulates the p53 signaling pathway by degrading 14-3-3 sigma and stabilizing MDM2. CARP1 does not localize to membranes in the cell and is involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8 and caspase 10. CARP1 contains an N-terminal FYVE-like domain and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1315370143 524 ENCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRKEIVSRI 569
Cdd:cd16706     4 DNLCRICMDAVIDCVLLECGHMVTCTKCGKRMSECPICRQYVVRAV 49

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein 1A (NEURL1A) and similar proteins; NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of the Drosophila neuralized (D-neu) protein. It functions as an E3 ubiquitin-protein ligase that directly interacts with and monoubiquitinates cytoplasmic polyadenylation element-binding protein 3 (CPEB3), an RNA binding protein and a translational regulator of local protein synthesis, which facilitates hippocampal plasticity and hippocampal-dependent memory storage. It also acts as a potential tumor suppressor that causes apoptosis and downregulates Notch target genes in the medulloblastoma. NEURL1A contains two neuralized homology regions (NHRs) responsible for Neural-ligand interactions and a modified C3HC5-type RING-HC finger required for ubiquitin ligase activity. The C3HC5-type RING-HC finger is distinguished from typical C3HC4-type RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQLE-----TCPLCRKEIVSRIR 570
Cdd:cd16785     7 CTICYENAVDTVIYTCGHMCLCYACGLRLKkmlnaCCPICRRAIKDIIK 55

RING finger, HC subclass, found in Dictyostelium discoideum Cbl-like protein A (CblA) and similar proteins; CblA is a Dictyostelium homolog of the Cbl proteins which are multi-domain proteins acting as key negative regulators of various receptor and non-receptor tyrosine kinase signaling. CblA upregulates STATc tyrosine phosphorylation by downregulating PTP3, the protein tyrosine phosphatase responsible for dephosphorylating STATc. STATc is a signal transducer and activator of transcription protein. Like other Cbl proteins, CblA contains a tyrosine-kinase-binding domain (TKB), a proline-rich domain, a C3HC4-type RING-HC finger, and an ubiquitin-associated (UBA) domain. TKB, also known as a phosphotyrosine binding PTB domain, is composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain. This family also includes Drosophila melanogaster defense repressor 1 (Dnr1) that was identified as an inhibitor of Dredd activity in the absence of a microbial insult in Drosophila S2 cells. It inhibits the Drosophila initiator caspases Dredd and Dronc. Moreover, Dnr1 acts as a negative regulator of the Imd (immune deficiency) innate immune-response pathway. Its mutations cause neurodegeneration in Drosophila by activating the innate immune response in the brain. Dnr1 contains a FERM N-terminal domain followed by a region rich in glutamine and serine residues, a central FERM domain, and a C-terminal C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1315370143 525 NCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRKEIvSRIRQI 572
Cdd:cd16501     6 DLCVVCMDAPIDTVFLECGHLACCRLCSKRLRVCPICRQPI-SRVVRI 52

RING finger, HC subclass, found in E3 ubiquitin-protein ligase XIAP, baculoviral IAP repeat-containing protein 8 (BIRC8) and similar proteins; XIAP, also known as baculoviral IAP repeat-containing protein 4 (BIRC4), IAP-like protein (ILP), inhibitor of apoptosis protein 3 (IAP-3), or X-linked inhibitor of apoptosis protein (X-linked IAP), is a potent suppressor of apoptosis that directly inhibits specific members of the caspase family of cysteine proteases, including caspase-3, -7, and -9. It promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. The ubiquitin-protein ligase (E3) activity of XIAP also exhibits in the ubiquitination of second mitochondria-derived activator of caspases (Smac). The mitochondrial proteins, Smac/DIABLO and Omi/HtrA2, can inhibit the antiapoptotic activity of XIAP. XIAP has also been implicated in several intracellular signaling cascades involved in the cellular response to stress, such as the c-Jun N-terminal kinase (JNK), the nuclear factor-kappaB (NF-kappaB), and the transforming growth factor-beta (TGF-beta) pathways. Moreover, XIAP can regulate copper homeostasis by interacting with MURR1. BIRC8, also known as inhibitor of apoptosis-like protein 2, IAP-like protein 2, ILP-2, or testis-specific inhibitor of apoptosis, is a tissue-specific homolog of E3 ubiquitin-protein ligase XIAP. It has been implicated in the control of apoptosis in the testis by direct inhibition of caspase 9. Both XIAP and BIRC8 contain three N-terminal baculoviral IAP repeat (BIR) domains, a ubiquitin-association (UBA) domain and a C3HC4-type RING-HC finger at the carboxyl terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1315370143 523 RENCCSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCRKEIVSRIR 570
Cdd:cd16714    13 EEKLCKICMDRNISIVFIPCGHLVTCKQCAEALDKCPICCTVITFKQK 60

RING finger, HC subclass, found in RNA-binding proteins of the evolutionarily-conserved MEX-3 family; MEX-3 phosphoproteins are found in vertebrates. They are mediators of post-transcriptional regulation in different organisms, and have been implicated in many core biological processes, including embryonic development, epithelial homeostasis, immune responses, metabolism, and cancer. They contain two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. They shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway. The RNA-binding protein MEX-3 from nematode Caenorhabditis elegans is the founding member of the MEX-3 family. Due to the lack of a RING-HC finger, it is not included here.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQL-----ETCPLCRKEIVSRIR 570
Cdd:cd16518     3 CVVCFESEVVAALVPCGHNLFCMECANRIceksdPECPVCHTPVTQAIR 51

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 1315370143 526 CCSLCCDEVADTQLKPCGHSdLCMDCALQL-----ETCPLC 561
Cdd:cd16449     2 ECPICLERLKDPVLLPCGHV-FCRECIRRLlesgsIKCPIC 41

RING finger, HC subclass, found in RNA-binding protein MEX3C; MEX3C, also known as RING finger and KH domain-containing protein 2 (RKHD2), or RING finger protein 194 (RNF194), is an RNA-binding phosphoprotein that acts as a suppressor of chromosomal instability. It functions as an ubiquitin E3 ligase responsible for the post-transcriptional, HLA-A allotype-specific regulation of MHC class I molecules (MHC-I). It also modifies retinoic acid inducible gene-1 (RIG-I) in stress granules and plays a critical role in eliciting antiviral immune responses. Moreover, MEX3C plays an essential role in normal postnatal growth via enhancing the local expression of insulin-like growth factor 1 (IGF1) in bone. It may also be involved in metabolic regulation of energy balance. MEX3C contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3C shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQ-----LETCPLCRKEIVSRIR 570
Cdd:cd16722     4 CVICFENEVIAALVPCGHNLFCMECANKicekeTPSCPVCQTAVTQAIQ 52

SPRY domain in heterogeneous nuclear ribonucleoprotein U-like (hnRNP) protein 1; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of heterogeneous nuclear ribonucleoprotein U-like (hnRNP) protein 1 (also known as HNRPUL1 ) which is a major constituent of nuclear matrix or scaffold and binds directly to DNA sequences through the N-terminal acidic region named serum amyloid P (SAP). Its function is specifically modulated by E1B-55kDa in adenovirus-infected cells. HNRPUL1 also participates in ATR protein kinase signaling pathways during adenovirus infection. Two transcript variants encoding different isoforms have been found for this gene. When associated with bromodomain-containing protein 7 (BRD7), it activates transcription of glucocorticoid-responsive promoter in the absence of ligand-stimulation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 331 LKISPHGLEARCD-----ASSFESVRCTFCVDTGVWYYEVTVV-------------TSGVMQIGWATRDSKFLnhegygI 392
Cdd:cd12884    12 LKISKDRYSASPLtdegfAYLWAGARATYGVTKGKVCFEVKVTenlpvkhlpteetDPHVVRVGWSVDSSSLQ------L 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 393 GDDEYSCAYDGcRQLIWYNARSKPHVHPcWKEGDTVGFLLDLN--EKQMIFFLNGNQLPPEKQVFSSTVSGffaAASF-- 468
Cdd:cd12884    86 GEEEFSYGYGS-TGKKSTNCKFEDYGEP-FGENDVIGCYLDFEsePVEISFSKNGKDLGVAFKISKEELGG---KALFph 160

                         170
                  ....*....|....*.
gi 1315370143 469 --MSYQQCEFNFGARP 482
Cdd:cd12884   161 vlTKNCAVEVNFGQKE 176

Modified RING finger, HC subclass (C3HC5-type), found in RING finger proteins, RNF26, RNF197 (CGRRF1), RNF156 (MGRN1), RNF157 and similar proteins; This subfamily corresponds to a group of RING finger proteins containing a modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain. Cell growth regulator with RING finger domain protein 1 (CGRRF1), also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination after viral infection and promoting degradation of IRF3, another important component required for virus-triggered interferon induction. Mahogunin ring finger-1 (MGRN1), also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase MGRN1. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis.

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQL--ETCPLCR 562
Cdd:cd16649     3 CVVCLENPASVLLLPCRHLCLCEVCAKGLrgKTCPICR 40

first RING finger, HC subclass, found in mind bomb 1 (MIB1) and similar proteins; MIB1, also known as DAPK-interacting protein 1 (DIP-1) or zinc finger ZZ type with ankyrin repeat domain protein 2, is a large, multi-domain E3 ubiquitin-protein ligase that promotes ubiquitination of the cytoplasmic tails of Notch ligands, and thus plays an essential role in controlling metazoan development by Notch signaling. It is also involved in Wnt/beta-catenin signaling and nuclear factor (NF)-kappaB signaling, and has been implicated in innate immunity, neuronal function, genomic stability, and cell death. MIB1 contains an MZM region with two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region consisting of three C3HC4-type RING-HC fingers. This model corresponds to the first RING-HC finger.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCR 562
Cdd:cd16724     3 CMVCSDMKRDTLFGPCGHIATCSLCSPRVKKCLICK 38

Modified RING finger, HC subclass (C3HC5-type), found in mahogunin RING finger protein 1 (MGRN1), RING finger protein 157 (RNF157) and similar proteins; MGRN1, also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. MGRN1 interacts with cytosolic prion proteins (PrPs) that are linked with neurodegeneration. It also interacts with expanded polyglutamine proteins, and suppresses misfolded polyglutamine aggregation and cytotoxicity. Moreover, MGRN1 inhibits melanocortin receptor signaling by competition with Galphas, suggesting a novel pathway for melanocortin signaling from the cell surface to the nucleus. MGRN1 also interacts with and ubiquitylates TSG101, a key component of the endosomal sorting complex required for transport (ESCRT)-I, and regulates endosomal trafficking. A null mutation in the gene encoding MGRN1 causes spongiform neurodegeneration, suggesting a link between dysregulation of endosomal trafficking and spongiform neurodegeneration. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase mahogunin ring finger-1 (MGRN1). In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis. Both MGRN1 and RNF157 contain a modified C3HC5-type RING-HC finger, and a functionally uncharacterized region, known as domain associated with RING2 (DAR2), N-terminal to the RING finger. The C3HC5-type RING-HC finger is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQLET----CPLCR 562
Cdd:cd16789     3 CVICLSDPRDTAVLPCRHLCLCSDCAEVLRYqsnkCPICR 42

RING finger, HC subclass, found in Arabidopsis thaliana MND1-interacting protein 1 (MIP1) and similar proteins; This subfamily includes Arabidopsis thaliana MIP1, RING finger protein 4 (RF4) and RING finger protein 298 (RF298). MIP1 interacts with MND1, HOP2 and XRI1. RF4 and RF298 are putative E3 ubiquitin-protein ligase that may mediate E2-dependent protein ubiquitination. Members of this subfamily contain a typical C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1315370143 523 RENCCSLCCDEVADTQLKPCGHSDLCMDCALQLE-----TCPLCRKEIVSRIR 570
Cdd:cd23128     2 RERECVMCMEEERSVVFLPCAHQVVCSGCNDLHEkkgmrECPSCRGEIQERIR 54

RING finger, HC subclass, found in RNA-binding protein MEX3A; MEX3A, also known as RING finger and KH domain-containing protein 4 (RKHD4), is an RNA-binding phosphoprotein that localizes in P-bodies and stress granules, which are two structures involved in the storage and turnover of mRNAs. It has been implicated in the regulation of tumorigenesis. It controls the polarity and stemness of intestinal epithelial cells through the post-transcriptional regulation of the homeobox transcription factor CDX2, which plays a crucial role in intestinal cell fate specification, both during normal development and in tumorigenic processes involving intestinal reprogramming. Moreover, it exhibits a transforming activity when overexpressed in gastric epithelial cells. MEX3A contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3A shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQL-----ETCPLCRKEIVSRIRQIS 573
Cdd:cd16720     5 CMVCFESEVTAALVPCGHNLFCMECAVRIcernePECPVCHALATQAIRIFS 56

RING finger, HC subclass, found in Arabidopsis thaliana protein XB3 homolog 1 (XBAT31) and similar proteins; XBAT31, also called ankyrin repeat domain and RING finger-containing protein XBAT31, or RING-type E3 ubiquitin transferase XB31, has no E3 ubiquitin-protein ligase activity observed when associated with the E2 enzyme UBC8 in vitro. XBAT31 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1315370143 524 ENCCSLCCDEVADTQLKPCGHSdLCMDCALQL---------------ETCPLCRKEIVS 567
Cdd:cd23144     6 EDVCCICFEHLCTIEIKDCGHQ-MCATCALKLcchnkpnpssspprpPACPFCRQDIAS 63

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-c and similar proteins; Cbl-c, also known as RING finger protein 57 (RNF57), SH3-binding protein Cbl-3, SH3-binding protein Cbl-c, or signal transduction protein Cbl-c, is an E3 ubiquitin-protein ligase expressed exclusively in epithelial cells. It contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a C3HC4-type RING-HC finger, and a short proline-rich region, but lacks the ubiquitin-associated (UBA) leucine zipper motif that are present in Cbl and Cbl-b. Cbl-c acts as a regulator of epidermal growth factor receptor (EGFR)-mediated signal transduction. It also suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Moreover, Cbl-c ubiquitinates and downregulates RETMEN2A and implicates Enigma (PDLIM7) as a positive regulator of RETMEN2A by blocking Cbl-mediated ubiquitination and degradation. The ubiquitin ligase activity of Cbl-c is increased via the interaction of its RING-HC finger domain with a LIM domain of the paxillin homolog, hydrogen peroxide induced construct 5 (Hic-5).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1315370143 527 CSLCCDEVADTQLKPCGHSdLCMDC--ALQ---LETCPLCRKEIVSR 568
Cdd:cd16710    16 CKICAERDKDVRIEPCGHL-LCSCClaAWQhsdSQTCPFCRCEIKGR 61

RING finger, HC subclass, found in Casitas B-lineage lymphoma (Cbl) proteins; The Cbl adaptor protein family contains a small class of RING-type E3 ubiquitin ligases with oncogenic activity, which is represented by three mammalian members, c-Cbl, Cbl-b and Cbl-c, as well as two invertebrate Cbl-family proteins, D-Cbl in Drosophila and Sli-1 in C. elegans. Cbl proteins function as potent negative regulators of various signaling cascades in a wide range of cell types. They play roles in ubiquitinating activated tyrosine kinases and targeting them for degradation. D-Cbl associates with the Drosophila epidermal growth factor receptor (EGFR) and overexpression of D-Cbl in the eye of Drosophila embryos inhibits EGFR-dependent photoreceptor cell development. Sli-1 is a negative regulator of the Let-23 receptor tyrosine kinase, an EGFR homolog, in vulva development. Cbl proteins in this subfamily consist of a highly conserved N-terminal half that includes a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain) and a C3HC4-type RING-HC finger, both of which are required for Cbl-mediated downregulation of RTKs, and a divergent C-terminal region.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 1315370143 527 CSLCCDEVADTQLKPCGHSdLCMDCALQLE-----TCPLCR 562
Cdd:cd16502     4 CKICAENDKDVRIEPCGHL-LCTPCLTSWQdsdgqTCPFCR 43

Modified RING finger, HC subclass (C3HC5-type), found in cell growth regulator with RING finger domain protein 1 (CGRRF1) and similar proteins; CGRRF1, also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. CGRRF1 contains a C-terminal modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1315370143 527 CSLCCDEVADTQLKPCGHSDLCMDCALQLETCPLCR 562
Cdd:cd16787     3 CVVCQNAPVNRVLLPCRHACVCDECFKRLQRCPMCR 38

SPRY domain in Ran binding proteins 9 and 10; This family includes SPRY domain in Ran binding protein (RBP or RanBPM) 9 and 10, and similar proteins. RanBP9 (also known as RanBPM), a binding partner of Ran, is a small Ras-like GTPase that exerts multiple functions via interactions with various proteins. RanBP9 and RanBP10 also act as androgen receptor (AR) coactivators. Both consist of the N-terminal proline- and glutamine-rich regions, the SPRY domain, and LisH-CTLH and CRA motifs. SPRY domain of RanBPM forms a complex with CD39, a prototypic member of the NTPDase family, thus down-regulating activity substantially. RanBP10 enhances the transcriptional activity of AR in a ligand-dependent manner and exhibits a protein expression pattern different from RanBPM in various cell lines. RanBP10 is highly expressed in AR-positive prostate cancer LNCaP cells, while RanBPM is abundant in WI-38 and MCF-7 cells.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1315370143 343 DASSfesVRCTFCV--DTGVWYYEVTVVTSGV---MQIGWATRDSKfLNH------EGYGI-GDD--EYSCAYDGcrqli 408
Cdd:cd12909    10 DAAA---VRANHPIppQCGIYYFEVKIISKGRdgyIGIGFSTKDVN-LNRlpgwepHSWGYhGDDghSFCSSGTG----- 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1315370143 409 wynarsKPHvHPCWKEGDTVGFLLDLNEKQMIFFLNGNQLP 449
Cdd:cd12909    81 ------KPY-GPTFTTGDVIGCGINFRDNTAFYTKNGVNLG 114

second RING finger, HC subclass, found in mind bomb 2 (MIB2) and similar proteins; MIB2, also known as novel zinc finger protein (Novelzin), putative NF-kappa-B-activating protein 002N, skeletrophin, or zinc finger ZZ type with ankyrin repeat domain protein 1, is a large, multi-domain E3 ubiquitin-protein ligase that promotes ubiquitination of the cytoplasmic tails of Notch ligands. Especially, it promotes Delta ubiquitylation and endocytosis in Notch activation. Overexpression of MIB2, activates NF-kappaB and interferon-stimulated response element (ISRE) reporter activity. Moreover, MIB2 acts as a novel component of the activated B-cell CLL/lymphoma 10 (BCL10) complex and controls BCL10-dependent NF-kappaB activation. It also functions as a founder myoblast-specific protein that regulates myoblast fusion and muscle stability. MIB2 contains an MZM region with two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region consisting of two C3HC4-type RING-HC fingers. This model corresponds to the second RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1315370143 527 CSLCCDEVADTQLKpCGHSDlCMDCALQLETCPLCRKEIVSRIR 570
Cdd:cd16728     7 CPICIDNHIKLVFQ-CGHGS-CIECSSALKACPICRQAIRERIQ 48