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 2017832174 522 RENCCTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQEI 564
Cdd:cd16566     1 REDSCTLCFDKVADTELRPCGHSGFCMECALQLETCPLCRQPI 43

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2017832174 359 VWYYEVTV--ITSGVMQIGWATKDSKFLNHEGygIGDDEYSCAYDGCRQLIWYNAKSKPHQHPCWKEGDTVGFLLDLHKK 436
Cdd:pfam00622   1 RHYFEVEIfgQDGGGWRVGWATKSVPRKGERF--LGDESGSWGYDGWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2017832174 437 LMIFSLNGHQLPPEKQVFTsATSGFFAAASFMSYQQCEFNFG 478
Cdd:pfam00622  79 TISFTKNGKSLGYAFRDVP-FAGPLFPAVSLGAGEGLKFNFG 119

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 2017832174 522 RENCCTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQEI 564
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 2017832174 358 GVWYYEVTVIT--SGVMQIGWATKDSKFLNHEGYGigDDEYSCAYDGCRQLIWYNAKSKPHQHPcWKEGDTVGFLLDLHK 435
Cdd:cd11709     1 GKWYWEVRVDSgnGGLIQVGWATKSFSLDGEGGVG--DDEESWGYDGSRLRKGHGGSSGPGGRP-WKSGDVVGCLLDLDE 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 2017832174 436 KLMIFSLNGHQLPPEKQVFTSATSGFFAAASFMSYQQCEFN 476
Cdd:cd11709    78 GTLSFSLNGKDLGVAFTNLFLKGGGLYPAVSLGSGQGVTIN 118

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2017832174 359 VWYYEVTV--ITSGVMQIGWATKDSKFLNHEGygIGDDEYSCAYDGCRQLIWYNAKSKPHQHPCWKEGDTVGFLLDLHKK 436
Cdd:pfam00622   1 RHYFEVEIfgQDGGGWRVGWATKSVPRKGERF--LGDESGSWGYDGWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2017832174 437 LMIFSLNGHQLPPEKQVFTsATSGFFAAASFMSYQQCEFNFG 478
Cdd:pfam00622  79 TISFTKNGKSLGYAFRDVP-FAGPLFPAVSLGAGEGLKFNFG 119

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 2017832174 522 RENCCTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQEI 564
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 2017832174 348 SVRCTFCVDSGVWYYEVTVITSGVMQ-----IGWATKDSKFlnheGYGIGDDEYSCAY---DGCrqlIWYNAKSKPHQHP 419
Cdd:cd12872    18 MARANHGVREGKWYFEVKILEGGGTEtghvrVGWSRREASL----QAPVGYDKYSYAIrdkDGS---KFHQSRGKPYGEP 90

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2017832174 420 CWKEGDTVGFLLDLHKklMIFSLNGhqlppEKQ--VFT--SATSGFFAAAS-FMSyQQCEFNFGaKPFK 483
Cdd:cd12872    91 GFKEGDVIGFLITLPK--IEFFKNG-----KSQgvAFEdiYGTGGYYPAVSlYKG-ATVTINFG-PDFK 150

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2017832174 522 RENCCTLCCDEVADTELKPCGHSDLCMECALQLE----TCPLCRQEIKTR 567
Cdd:pfam13920   1 EDLLCVICLDRPRNVVLLPCGHLCLCEECAERLLrkkkKCPICRQPIESV 50

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 2017832174 355 VDSGVWYYEVTVI---TSGVMQIGWATKDSKFLNHegygIGDDEYSCAY---DGCrqlIWYNAKSKPHQHPCWKEGDTVG 428
Cdd:cd12885    11 PKVPVFYFEVTILdlgEKGIVSIGFCTSGFPLNRM----PGWEDGSYGYhgdDGR---VYLGGGEGENYGPPFGTGDVVG 83

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2017832174 429 FLLDLHKKLMIFSLNGHQLPPekqVFTSATSG-FFAAASFmSYQQCEF--NFG 478
Cdd:cd12885    84 CGINFKTGEVFFTKNGELLGT---AFENVVKGrLYPTVGL-GSPGVKVrvNFG 132

RING finger, HC subclass, found in myosin regulatory light chain interacting protein (MYLIP) and similar proteins; MYLIP, also known as inducible degrader of the low-density lipoprotein (LDL)-receptor (IDOL), or MIR, is an E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR, and LRP8. Its activity depends on E2 ubiquitin-conjugating enzymes of the UBE2D family. MYLIP stimulates clathrin-independent endocytosis and acts as a sterol-dependent inhibitor of cellular cholesterol uptake by binding directly to the cytoplasmic tail of the LDLR and promoting its ubiquitination via the UBE2D1/E1 complex. The ubiquitinated LDLR then enters the multivesicular body (MVB) protein-sorting pathway and is shuttled to the lysosome for degradation. Moreover, MYLIP has been identified as a novel ERM-like protein that affects cytoskeleton interactions regulating cell motility, such as neurite outgrowth. The ERM proteins includes ezrin, radixin, and moesin, which are cytoskeletal effector proteins linking actin to membrane-bound proteins at the cell surface. MYLIP contains an ERM-homology domain and a C-terminal C3HC4-type RING-HC finger.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQEI 564
Cdd:cd16523     5 CMVCCEEEINSAFCPCGHMVCCESCAAQLQSCPVCRSRV 43

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 2017832174 523 ENCCTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQ 562
Cdd:cd16510     1 EKLCKICMDREVNIVFLPCGHLVTCAQCAASLRKCPICRT 40

RING finger, HC subclass, found in leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) and similar proteins; LRSAM1, also known as Tsg101-associated ligase (TAL), or RIFLE, is an E3 ubiquitin-protein ligase that physically associates with, and selectively ubiquitylates, Tsg101, an E2-like molecule that regulates vesicular trafficking processes in yeast and mammals. It regulates a Tsg101-associated complex responsible for the sorting of cargo into cytoplasm-containing vesicles that bud at the multivesicular body and at the plasma membrane. LRSAM1 is a multidomain protein containing an N-terminal leucine-rich repeat (LRR), followed by several recognizable motifs, including an ezrin-radixin-moezin (ERM) domain, a coiled-coil (CC) region, a SAM domain, and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQEIKTRVR 569
Cdd:cd16515     4 CVVCMDAESQVIFLPCGHVCCCQTCSSSLSTCPLCRADITQRVR 47

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 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLE-----TCPLCRQEIK 565
Cdd:cd16785     7 CTICYENAVDTVIYTCGHMCLCYACGLRLKkmlnaCCPICRRAIK 51

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 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQL----ETCPLCRQEIK 565
Cdd:cd16552     4 CAICFHHTANTRLVPCGHSHFCGSCAWHIfrdtARCPVCRWQIE 47

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 2017832174 523 ENCCTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQEI 564
Cdd:cd16706     4 DNLCRICMDAVIDCVLLECGHMVTCTKCGKRMSECPICRQYV 45

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein 2 (CARP-2) and similar proteins; CARP-2, also known as rififylin, caspase regulator CARP2, FYVE-RING finger protein Sakura (Fring), RING finger and FYVE-like domain-containing protein 1, RING finger protein 189 (RNF189), or RING finger protein 34-like, is an endosome-associated E3 ubiquitin-protein ligase that targets internalized receptor interacting kinase (RIP) for proteasome-mediated degradation. It acts as a negative regulator of tumor necrosis factor (TNF)-induced nuclear factor (NF)-kappaB activation. It also regulates the p53 signaling pathway by degrading 14-3-3sigma and stabilizing MDM2. As a caspase regulator, CARP2 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. CARP2 contains an N-terminal FYVE-like domain and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2017832174 523 ENCCTLCCDEVADTELKPCGHSDLCMECALQLETCPLCRQ 562
Cdd:cd16707     2 ENLCKICMDSPIDCVLLECGHMVTCTKCGKRMSECPICRQ 41

RING finger, HC subclass, found in zinc finger protein 598 (ZNF598) and similar proteins; ZNF598 associates with eukaryotic initiation factor 4E (eIF4E) homologous protein from mammals (m4EHP) by binding to Grb10-interacting GYF protein 2 (GIGYF2). The m4EHP-GIGYF2 complex functions as a translational repressor and is essential for normal embryonic development of mammalian. ZNF598 harbors a C3HC4-type RING-HC finger at its N-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2017832174 524 NCCTLCCDEVADTELKPCGHSdLCMECALQLET------CPLCRQEIK 565
Cdd:cd16615     1 ETCVICCEEIEYFAVGPCNHP-VCYKCSLRMRVlykdkyCPICRTELD 47

RING finger, HC subclass, found in mind bomb MIB1, MIB2, and similar proteins; MIBs are large, multi-domain E3 ubiquitin-protein ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. They are also responsible for TBK1 K63-linked ubiquitination and activation, promoting interferon production and controlling antiviral immunity. Moreover, MIBs selectively control responses to cytosolic RNA and regulate type I interferon transcription. Both MIB1 and MIB2 have similar domain architectures, which consist of 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, where MIB1 and MIB2 contain three and two C3HC4-type RING-HC fingers, respectively. This model corresponds to the first RING-HC finger of MIB1 and MIB2, as well as the second RING-HC finger of MIB1.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLETCPLCR 561
Cdd:cd16519     3 CRVCSDKKALVLFQPCGHVVACEECSLRMKKCLQCK 38

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 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQL-----ETCPLCRQ 562
Cdd:cd16518     3 CVVCFESEVVAALVPCGHNLFCMECANRIceksdPECPVCHT 44

RING finger, HC subclass, found in RNA-binding protein MEX3B; MEX3B, also known as RING finger and KH domain-containing protein 3 (RKHD3), or RING finger protein 195 (RNF195), 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 regulates the spatial organization of the Rap1 pathway that orchestrates Sertoli cell functions. It has a 3' long conserved untranslated region (3'LCU)-mediated fine-tuning system for mRNA regulation in early vertebrate development such as anteroposterior (AP) patterning and signal transduction. MEX3B 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, MEX3B shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQL-----ETCPLCRQEIKTRVRQIS 572
Cdd:cd16721     7 CSICFESEVIAALVPCGHNLFCMECANRIceknePQCPVCHAAVTQAIRIFS 58

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 2017832174 525 CCTLCCDEVADTELKPCGHSdLCMECALQL-----ETCPLC 560
Cdd:cd16449     2 ECPICLERLKDPVLLPCGHV-FCRECIRRLlesgsIKCPIC 41

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 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLETCPLCR 561
Cdd:cd16787     3 CVVCQNAPVNRVLLPCRHACVCDECFKRLQRCPMCR 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.

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gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLET----CPLCR 561
Cdd:cd16789     3 CVICLSDPRDTAVLPCRHLCLCSDCAEVLRYqsnkCPICR 42

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 2017832174 342 DASSfesVRCTFCV--DSGVWYYEVTVITSGV---MQIGWATKDSKfLNH------EGYGI-GDD--EYSCAYDGcrqli 407
Cdd:cd12909    10 DAAA---VRANHPIppQCGIYYFEVKIISKGRdgyIGIGFSTKDVN-LNRlpgwepHSWGYhGDDghSFCSSGTG----- 80

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gi 2017832174 408 wynaksKPHQhPCWKEGDTVGFLLDLHKKLMIFSLNGHQLP 448
Cdd:cd12909    81 ------KPYG-PTFTTGDVIGCGINFRDNTAFYTKNGVNLG 114

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.

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gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQL-----ETCPLCRQEIKTRVRQIS 572
Cdd:cd16720     5 CMVCFESEVTAALVPCGHNLFCMECAVRIcernePECPVCHALATQAIRIFS 56

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.

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gi 2017832174 526 CTLCCDEVADTELKpCGHSDlCMECALQLETCPLCRQEIKTRVR 569
Cdd:cd16728     7 CPICIDNHIKLVFQ-CGHGS-CIECSSALKACPICRQAIRERIQ 48

Prokaryotic RING finger family 4; RING finger family domain found sporadically in bacteria. The finger is fused to an N-terminal alpha-helical domain, ROT/Trove-like repeats and a C-terminal TerD domain. The architecture suggests a possible role in an RNA-processing complex.

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gi 2017832174 526 CTLCCDEVADTELKPCGHSdLCMEC--ALQLETCPLCRQEI 564
Cdd:pfam14447   1 CVLCGRNGTVHALIPCGHL-VCRDCfdGSDFSACPICRRRI 40

PRY/SPRY domain in tripartite motif-containing (TRIM) proteins, including TRIM14-like, TRIM16-like, TRIM25-like, TRIM47-like, TRIM65 and RNF135, and stonustoxin; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several Class I TRIM proteins, including TRIM14, TRIM16 and TRIM25, TRIM47 as well as RING finger protein RNF135 and stonustoxin, a secreted poisonous protein of the stonefish Synanceja horrida. TRIM16 (also known as estrogen-responsive B box protein or EBBP) has E3 ubiquitin ligase activity. It is a regulator of keratinocyte differentiation and a tumor suppressor in retinoid-sensitive neuroblastoma. TRIM25 (also called Efp) ubiquitinates the N terminus of the viral RNA receptor retinoic acid-inducible gene-I (RIG-I) in response to viral infection, leading to activation of the RIG-I signaling pathway, thus resulting in type I interferon production to limit viral replication. It has been shown that the influenza A virus targets TRIM25 and disables its antiviral function. TRIM47, also known as GOA (Gene overexpressed in astrocytoma protein) or RNF100 (RING finger protein 100), is highly expressed in kidney tubular cells, but low expressed in most tissue. It is overexpressed in astrocytoma tumor cells and plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. RNF135 ubiquitinates RIG-I (retinoic acid-inducible gene-I) to promote interferon-beta induction during the early phase of viral infection. Stonustoxin (STNX) is a hypotensive and lethal protein factor that also possesses other biological activities such as species-specific hemolysis (due to its ability to form pores in the cell membrane) and platelet aggregation, edema-induction, and endothelium-dependent vasorelaxation (mediated by the nitric oxide pathway and activation of potassium channels). The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site.

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gi 2017832174 321 LNSNDVSEYLKISPYGLEARCDA---------SSFES--VRCTFCVDSGVWYYEVTVITSGVMQIGWATKDSKFLNHEGY 389
Cdd:cd12891     3 LDPNTAHNNLALSGDLKTVTCSSenqhypdspERFTHsqVLSTQSFSSGRHYWEVEVSESGGWSVGVAYPSIERKGDESR 82

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gi 2017832174 390 gIGDDEYSCAYDGCRQLI--WYNAKSKPHQHPCwkeGDTVGFLLDL 433
Cdd:cd12891    83 -IGRNDKSWCLEWQDKSFsaWHNNEETPLPSVS---SRRLGVYLDY 124

RING finger, HC subclass, found in mind bomb MIB1, MIB2, RGLG1, RGLG2, and similar proteins; MIBs are large, multi-domain E3 ubiquitin-protein ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. They are also responsible for TBK1 K63-linked ubiquitination and activation, promoting interferon production and controlling antiviral immunity. Moreover, MIBs selectively control responses to cytosolic RNA and regulate type I interferon transcription. Both MIB1 and MIB2 have similar domain architectures, which consist of 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, where MIB1 and MIB2 contain three and two C3HC4-type RING-HC fingers, respectively. This model corresponds to the third RING-HC finger of MIB1, as well as the second RING-HC finger of MIB2. In addition to MIB1 and MIB2, the RING-HC fingers of RING domain ligase RGLG1, RGLG2 and similar proteins from plant are also included in this model. RGLG1 is a ubiquitously expressed E3 ubiquitin-protein ligase that interacts with UBC13 and, together with UBC13, catalyzes the formation of K63-linked polyubiquitin chains, which is involved in DNA damage repair. RGLG1 mediates the formation of canonical, K48-linked polyubiquitin chains that target proteins for degradation. It also regulates apical dominance by acting on the auxin transport proteins abundance. RGLG1 has overlapping functions with its closest sequelog, RGLG2. They both function as RING E3 ligases that interact with ethylene response factor 53 (ERF53) in the nucleus and negatively regulate the plant drought stress response. All RGLG proteins contain a Von Willebrand factor type A (vWA) domain and a C3HC4-type RING-HC finger.

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gi 2017832174 525 CCTLCCDEVADTELKpCGHSdLCMECALQLETCPLCRQEI 564
Cdd:cd16520     2 LCPICMERKKNVVFL-CGHG-TCQKCAEKLKKCPICRKPI 39

Modified RING finger, HC subclass (C3HC5-type), found in RING finger protein 26 (RNF26) and similar proteins; 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 of MITA after viral infection, and promoting the degradation of IRF3, another important component required for virus-triggered interferon induction. Although RNF26 substrates of ubiquitination remain unclear at present, RNF26 upregulation in gastric cancer might be implicated in carcinogenesis through dysregulation of growth regulators. RNF26 contains an N-terminal leucine zipper domain and 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.

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gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLET-------CPLCRQEIKT 566
Cdd:cd16788     8 CVICQDQSKTVLILPCRHMCLCRQCANILLQqpvyrrnCPLCRTMILQ 55

first 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. 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 first RING-HC finger.

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gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLETCPLC 560
Cdd:cd16726     3 CLVCSELAALVRFEPCQHSIVCEECARRMKKCIKC 37

RING finger, HC subclass, found in Arabidopsis thaliana SP1-like protein 2 (SPL2) and similar proteins; SPL2, also known as RING-type E3 ubiquitin transferase SPL2, acts as an E3 ubiquitin-protein ligase that mediates E2-dependent protein ubiquitination. SPL2 contains a typical C3HC4-type RING-HC finger.

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gi 2017832174 526 CTLCCDEVADTELKPCGHSDLCMECALQLET-----CPLCRQ 562
Cdd:cd23145     6 CVVCLLRRRRVAFIECGHRVCCELCARRVTReanprCPVCRQ 47