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 212640921 508 PEDYCTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRKPI 550
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 212640921  342 VWYYEATVL--TSGVMQIGLATKRSRFLNHEGygIGDDASSVAYDGCRQLVWYNAKSHKHEHENWQPGDVIGVLLNIPEG 419
Cdd:pfam00622   1 RHYFEVEIFgqDGGGWRVGWATKSVPRKGERF--LGDESGSWGYDGWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 212640921  420 EVVFYLNGTPLkepETEFLSNRQpSEGVFAAASFMSFQQCRFNFG 464
Cdd:pfam00622  79 TISFTKNGKSL---GYAFRDVPF-AGPLFPAVSLGAGEGLKFNFG 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 212640921 508 PEDYCTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRKPI 550
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 212640921  342 VWYYEATVL--TSGVMQIGLATKRSRFLNHEGygIGDDASSVAYDGCRQLVWYNAKSHKHEHENWQPGDVIGVLLNIPEG 419
Cdd:pfam00622   1 RHYFEVEIFgqDGGGWRVGWATKSVPRKGERF--LGDESGSWGYDGWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 212640921  420 EVVFYLNGTPLkepETEFLSNRQpSEGVFAAASFMSFQQCRFNFG 464
Cdd:pfam00622  79 TISFTKNGKSL---GYAFRDVPF-AGPLFPAVSLGAGEGLKFNFG 119

SPRY domain at N-terminus of ring finger protein 123; This SPRY domain is found at the N-terminus of RING finger protein 123 domain (also known as E3 ubiquitin-protein ligase RNF123). The ring finger domain motif is present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. RNF123 displays E3 ubiquitin ligase activity toward the cyclin-dependent kinase inhibitor p27 (Kip1).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212640921 331 SVRCTFEVMDGVWYYEATVLTSGVMQIGLATKRSRFLNHEgyGIGDDASSVAYDGCRQLVWyNAKSHKHeHENWQPGDVI 410
Cdd:cd12882    1 SIRANACVYKGKWMYEVTLGTKGIMQIGWATISCRFTQEE--GVGDTRDSYAYDGNRVRKW-NVSTQKY-GEPWVAGDVI 76

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 212640921 411 GVLLNIPEGEVVFYLNGTPLKEPETEFlsNRQPSEGVFAAASFMSFQQCRFNFG 464
Cdd:cd12882   77 GCCIDLDKGTISFYRNGRSLGVAFDNV--RRGPGLAYFPAVSLSFGERLELNFG 128

SPRY domain 2 (SPRY2) of ryanodine receptor (RyR); This SPRY domain (SPRY2) is the second 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, The SPRY2 domain has been shown to bind to the dihydropryidine receptor (DHPR) II-III loop and the ASI region of RyR1

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212640921 335 TFEVMDGVWYYEATVLTSGVMQIGLATKRSRflnhEGYGIGDDASSVAYDGCRQLVWYNakSHKHEHENWQPGDVIGVLL 414
Cdd:cd12878    8 TYAVTSGKWYFEFEVLTSGYMRVGWARPGFR----PDLELGSDDLSYAFDGFLARKWHQ--GSESFGKQWQPGDVVGCML 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 212640921 415 NIPEGEVVFYLNGTPLKEP---ETEFlSNRQPSEGVFAAASFMSFQQCRFNFG 464
Cdd:cd12878   82 DLVDRTISFTLNGELLIDSsgsEVAF-KDIEIGEGFVPACSLGVGQKGRLNLG 133

SPRY domain associated with DEAD box gene DDX1; This SPRY domain is associated with the DEAD box gene, DDX1, an RNA-dependent ATPase involved in HIV-1 Rev function and virus replication. It is suggested that DDX1 acts as a cellular cofactor by promoting oligomerization of Rev on the Rev response element (RRE). DDX1 RNA is overexpressed in breast cancer, data showing a strong and independent association between poor prognosis and deregulation of the DEAD box protein DDX1, thus potentially serving as an effective prognostic biomarker for early recurrence in primary breast cancer. DDX1 also interacts with RelA and enhances nuclear factor kappaB-mediated transcription. DEAD-box proteins are associated with all levels of RNA metabolism and function, and have been implicated in translation initiation, transcription, RNA splicing, ribosome assembly, RNA transport, and RNA decay.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212640921 304 LNHEDVSEYLKIGPDGLEARC-DVSSFESVRCTFEVM-DGVWYYEATVLTSGVMQIGLATKRSRFlnhegyGIGDDASSV 381
Cdd:cd12873    1 MNPYDRDAALAISPDGLLCQSrEEKGWQGCRATKGVKgKGKYYYEVTVTDEGLCRVGWSTEDASL------DLGTDKFGF 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212640921 382 AYDGCRQlvwynaKSHKHEHENW----QPGDVIGVLLNIPEGEVVFYLNGTPLkePETEFLSNRQPSEGVFAAASFMSfQ 457
Cdd:cd12873   75 GYGGTGK------KSHGRQFDDYgepfGLGDVIGCYLDLDNGTISFSKNGKDL--GKAFDIPPHLRNSALFPAVCLKN-A 145

                        170
                 ....*....|
gi 212640921 458 QCRFNFGASR 467
Cdd:cd12873  146 EVEFNFGDKP 155

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 212640921  509 EDYCTICFAAPGSTTLLPCNHDGFCSDCCNMM----DHCPLCRKPIEER 553
Cdd:pfam13920   2 DLLCVICLDRPRNVVLLPCGHLCLCEECAERLlrkkKKCPICRQPIESV 50

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 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCR 547
Cdd:cd16787    3 CVVCQNAPVNRVLLPCRHACVCDECFKRLQRCPMCR 38

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 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMM----DHCPLCRKPIEERIQ 555
Cdd:cd16647    4 CVICYERPVDTVLYRCGHMCMCYDCALQLkrrgGSCPICRAPIKDVIK 51

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 212640921 509 EDYCTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRKPIEERIQ 555
Cdd:cd16515    1 ESECVVCMDAESQVIFLPCGHVCCCQTCSSSLSTCPLCRADITQRVR 47

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 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMMDH----CPLCR 547
Cdd:cd16789    3 CVICLSDPRDTAVLPCRHLCLCSDCAEVLRYqsnkCPICR 42

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
                 ....*....|....*....|....*....|....*..
gi 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRK 548
Cdd:cd16510    4 CKICMDREVNIVFLPCGHLVTCAQCAASLRKCPICRT 40

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 212640921 510 DYCTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRKPI 550
Cdd:cd16501    6 DLCVVCMDAPIDTVFLECGHLACCRLCSKRLRVCPICRQPI 46

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
                 ....*....|....*....|....*....|....*....|....*....
gi 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMM-----DHCPLCRKPIEERIQ 555
Cdd:cd16721    7 CSICFESEVIAALVPCGHNLFCMECANRIceknePQCPVCHAAVTQAIR 55

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        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 212640921 498 RLELLEKEHIpedyCTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRKPIEERIQ 555
Cdd:cd16714    7 KLRRLQEEKL----CKICMDRNISIVFIPCGHLVTCKQCAEALDKCPICCTVITFKQK 60

Modified RING finger, HC subclass (C3HC5-type), found in mitochondrial-anchored protein ligase (MAPL) and similar proteins; MAPL, also known as MULAN, mitochondrial ubiquitin ligase activator of NFKB 1, E3 SUMO-protein ligase MUL1, E3 ubiquitin-protein ligase MUL1, growth inhibition and death E3 ligase (GIDE), putative NF-kappa-B-activating protein 266, or RING finger protein 218 (RNF218), is a multifunctional mitochondrial outer membrane protein involved in several processes specific to metazoan (multicellular animal) cells, such as NF-kappaB activation, innate immunity and antiviral signaling, suppression of PINK1/parkin defects, mitophagy in skeletal muscle, and caspase-dependent apoptosis. MAPL contains a unique BAM (beside a membrane)/GIDE (growth inhibition death E3 ligase) domain and a C-terminal modified cytosolic C3HC5-type RING-HC finger which 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 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMMDH---CPLCRKPI 550
Cdd:cd16648    4 CVICLSNPRSCVFLECGHVCSCIECYEALPSpkkCPICRSFI 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 212640921 509 EDYCTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRK 548
Cdd:cd16707    2 ENLCKICMDSPIDCVLLECGHMVTCTKCGKRMSECPICRQ 41

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 212640921 509 EDYCTICFAAPGSTTLLPCNHDGFCSDCCNMMDHCPLCRKPIEERIQ 555
Cdd:cd16713    7 ERTCKVCMDKEVSIVFIPCGHLVVCTECAPSLRKCPICRATIKGTVR 53

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein 1B (NEURL1B); NEURL1B, also known as neuralized-2 (NEUR2) or neuralized-like protein 3, is a mammalian homolog of the Drosophila neuralized (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 through working cooperatively with another E3 ligase, Mind bomb-1 (Mib1), in Delta endocytosis to hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-positive vesicles. NEURL1B 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 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMMDH-----CPLCRKPIEERIQ 555
Cdd:cd16786    5 CTVCFDSEVDTVIYTCGHMCLCNSCGLKLKRqinacCPICRRVIKDVIK 53

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.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 212640921 512 CTICFAAPGSTTLLpCNHdGFCSDCCNMMDHCPLCRKPI 550
Cdd:cd16520    3 CPICMERKKNVVFL-CGH-GTCQKCAEKLKKCPICRKPI 39

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
                 ....*....|....*....|....*....|....*....|....*....
gi 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDC----CNMMD-HCPLCRKPIEERIQ 555
Cdd:cd16720    5 CMVCFESEVTAALVPCGHNLFCMECavriCERNEpECPVCHALATQAIR 53

RING finger, HC subclass, found in RING finger protein 123 (RNF123) and similar proteins; RNF123, also known as Kip1 ubiquitination-promoting complex protein 1 (KPC1), is an E3 ubiquitin-protein ligase that mediates ubiquitination and proteasomal processing of the nuclear factor-kappaB 1 (NF-kappaB1) precursor p105 to the p50 active subunit that restricts tumor growth. It also regulates degradation of heterochromatin protein 1alpha (HP1alpha) and 1beta (HP1beta) in lamin A/C knock-down cells. Moreover, RNF123, together with Kip1 ubiquitylation-promoting complex 2 (KPC2), forms the Kip1 ubiquitination-promoting complex (KPC), acting as a cytoplasmic ubiquitin ligase that regulates degradation of the cyclin-dependent kinase inhibitor p27 (Kip1) at the G1 phase of the cell cycle. RNF123 may also function as a clinically relevant, peripheral state marker of depression. RNF123 contains a C3HC4-type RING-HC finger at the C-terminus.

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                 ....*....|....*....|....*....|....*....|....*
gi 212640921 510 DYCTICFAAPGSTTLLPCNHDGfCSDCCN--MMDH--CPLCRKPI 550
Cdd:cd16541    1 DLCPICYAHPIDAVFLPCGHKS-CRSCINrhLMNNkeCFFCKATI 44

Ring finger domain;

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                  ....*....|....*....|....*....|....*....|...
gi 212640921  512 CTIC---FAAPGSTTLLPCNHdGFCSDC----CNMMDHCPLCR 547
Cdd:pfam13639   3 CPICleeFEEGDKVVVLPCGH-HFHRECldkwLRSSNTCPLCR 44

Modified RING finger, HC subclass (C3HC5-type), found in RING finger protein 157 (RNF157) and similar proteins; RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in 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. RNF157 contains 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 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMM----DHCPLCRKPIEERIQ 555
Cdd:cd16817    7 CVVCLSDVRDTLILPCRHLCLCNACADTLryqaNNCPICRLPFRALLQ 54

SPRY domain in the suppressor of cytokine signaling 3 (SOCS3) family; The SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) is composed of a central SPRY protein interaction domain and a C-terminal SOCS box. All four SPSB proteins interact with c-Met, the hepatocyte growth factor receptor, but SOCS3 regulates cellular response to a variety of cytokines such as leukemia inhibitory factor (LIF) and interleukin 6. SOCS3, along with SOCS1, are expressed by immune cells and cells of the central nervous system (CNS) and have the potential to impact immune processes within the CNS. In non-small cell lung cancer (NSCLC), SOCS3 is silenced and proline-rich tyrosine kinase 2 (Pyk2) is over-expressed; it has been suggested that SOCS3 could be an effective way to prevent the progression of NSCLC due to its role in regulating Pyk2 expression.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212640921 332 VRCTFEVMDGVWYYEATVL-----TSgvMQIGLATKRSRfLNHEGY----GIGDDASS--VAYDGcrqLVWYNAKSHKH- 399
Cdd:cd12876   35 VRGTKPLTNGQHYWEIKMSspvygTD--MMVGVGTKKAD-LHAYRYefcsLLGEDEESwgLSYKG---LLWHDGQSRPYt 108

                         90       100       110
                 ....*....|....*....|....*....|....
gi 212640921 400 ---EHEnwqpGDVIGVLLNIPEGEVVFYLNGTPL 430
Cdd:cd12876  109 spfGNQ----GTIIGVHLDMWRGTLTFYKNGKPL 138

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.

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                 ....*....|....*....|....*....|....*....|...
gi 212640921 512 CTIC---FAAPGSTTLLPCNHdGFCSDCCN----MMDHCPLCR 547
Cdd:cd16454    2 CAICleeFKEGEKVRVLPCNH-LFHKDCIDpwleQHNTCPLCR 43

Modified RING finger, HC subclass (C3HC5-type), found in mahogunin RING finger protein 1 (MGRN1) 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. Furthermore, MGRN1 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. MGRN1 contains a modified C3HC5-type RING-HC finger, a conserved PSAP motif necessary for interaction between MGRN1 and TSG101. In addition, MGRN1 harbors a functionally uncharacterized region, as known as the 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 212640921 512 CTICFAAPGSTTLLPCNHDGFCSDCCNMM----DHCPLCRKPIEERIQ 555
Cdd:cd16816   11 CVVCLSDLRDTLILPCRHLCLCNSCADTLryqaNNCPICRLPFRALLQ 58

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Hakai, zinc finger protein 645 (ZNF645), and similar proteins; Hakai, also known as Casitas B-lineage lymphoma-transforming sequence-like protein 1, RING finger protein 188 (RNF188), or c-Cbl-like protein 1 (CBLL1), is an E3 ubiquitin ligase that disrupts cell-cell contacts in epithelial cells and is upregulated in human colon and gastric adenocarcinomas. It was identified to mediate the posttranslational downregulation of E-cadherin (CDH1), a major component of adherens junctions in epithelial cells and a potent tumor suppressor. It also promotes ubiquitination of several other tyrosine-phosphorylated Src substrates, including cortactin (CTTN) and DOK1. Hakai acts as a homodimer arranged in an anti-parallel configuration with a novel HYB (Hakai pTyr-binding) domain that forms a phosphotyrosine-binding pocket. Each monomer contains a C3HC4-type RING-HC finger and a short pTyr-B domain that incorporates a novel, atypical C2H2-type Zn-finger coordination motif. Both domains are important for dimerization. ZNF645 is a novel testis-specific E3 ubiquitin-protein ligase that plays a role in sperm production and quality control. It has a structure similar to that of the c-Cbl-like protein Hakai. In contrast to Hakai, its HYB domain demonstrates different target specificities. It interacts with v-Src-phosphorylated E-cadherin, but not to cortactin.

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                 ....*....|....*....|....*....|....*.
gi 212640921 524 LLPCNHdGFCSDC-CNMMDHCPLCRKPIeERIQKTK 558
Cdd:cd16508   16 MIPCKH-VFCLDCaRLHDKICPRCDDPV-QRIEQCT 49

RING finger, HC subclass, found in RING finger and transmembrane domain-containing protein RNFT1, RNFT2, and similar proteins; Both RNFT1 and RNFT2 are multi-pass membrane proteins containing a C3HC4-type RING-HC finger. Their biological roles remain unclear.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 212640921 510 DYCTICFAAPGSTTLLPCNHDgFCSDCCNM-MDH---CPLCR 547
Cdd:cd16532    1 DICPICQDEFKDPVVLRCKHI-FCEDCVSEwFERertCPLCR 41