RING finger (Really Interesting New Gene) domain and U-box domain superfamily; 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 different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are 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 enable efficient transfer of ubiquitin from E2 to the substrates.

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gi 646397358  87 CSICFE----KPITYGLLVGCSHVFCINCIREWRapankSTEVVSSGVIKKCPYCR 138
Cdd:cd16521    3 CGICMEvvleKERRFGILSNCNHVFCLECIREWR-----SSKDFENSIVRSCPICR 53

RING finger, HC subclass, found in the makorin (MKRN) proteins; The MKRN protein subfamily includes ribonucleoproteins that are characterized by a variety of zinc-finger motifs, including typical arrays of one to four C3H1-type zinc fingers and a C3HC4-type RING-HC finger. Another motif rich in Cys and His residues (CH), with so far unknown function, is also generally present in MKRN proteins. MKRN proteins may have E3 ubiquitin ligase activity.

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                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 646397358  87 CSICFE----KPITYGLLVGCSHVFCINCIREWRapankSTEVVSSGVIKKCPYCR 138
Cdd:cd16521    3 CGICMEvvleKERRFGILSNCNHVFCLECIREWR-----SSKDFENSIVRSCPICR 53

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

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                  ....*....|....*....|....*....
gi 646397358   87 CSICFEKPITYGLLVGCSHVFCINCIREW 115
Cdd:pfam00097   1 CPICLEEPKDPVTLLPCGHLFCSKCIRSW 29

Uncharacterized conserved protein, contains RING and CCCH-type Zn-fingers [General function prediction only];

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 646397358  18 ICRYYSTSRGCFAGDKCKFLHgeqekitpfDRSKtciyYAQGYCRRGSQCWFKHVAPSTPQPASSSDDLCSIC---FEKP 94
Cdd:COG5152  143 VCKDYKETGYCGYGDSCKFLH---------DRSD----FKTGWKLNQEWNAEYEEAPVISGPGEKIPFLCGICkkdYESP 209

                         90       100
                 ....*....|....*....|...
gi 646397358  95 ItyglLVGCSHVFCINC-IREWR 116
Cdd:COG5152  210 V----VTECGHSFCSLCaIRKYQ 228

p28-like protein; Provisional

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 646397358  28 CFAGDKCKFLHGEQEKITPF-DRS-----------KTCIYYaqgycrRGSQCWFKhvapstpqpasssddLCSICFE--- 92
Cdd:PHA03096 131 CYKGKYCEYLHGDICDICEKyLLHptdikqryneqKTCLSY------QLRLLLSK---------------ICGICLEnik 189

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 646397358  93 -KPIT---YGLLVGCSHVFCINCIREWrapankSTEVVSSGVIKKCPYCRVEARFI 144
Cdd:PHA03096 190 aKYIIkkyYGILSEIKHEFNIFCIKIW------MTESLYKETEPENRRLNTVIVFI 239

RING finger, HC subclass, found in the makorin (MKRN) proteins; The MKRN protein subfamily includes ribonucleoproteins that are characterized by a variety of zinc-finger motifs, including typical arrays of one to four C3H1-type zinc fingers and a C3HC4-type RING-HC finger. Another motif rich in Cys and His residues (CH), with so far unknown function, is also generally present in MKRN proteins. MKRN proteins may have E3 ubiquitin ligase activity.

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                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 646397358  87 CSICFE----KPITYGLLVGCSHVFCINCIREWRapankSTEVVSSGVIKKCPYCR 138
Cdd:cd16521    3 CGICMEvvleKERRFGILSNCNHVFCLECIREWR-----SSKDFENSIVRSCPICR 53

RING finger, HC subclass, found in makorin-1 (MKRN1), makorin-3 (MKRN3), and similar proteins; MKRN1, also known as makorin RING finger protein 1 or RING finger protein 61 (RNF61), is an E3 ubiquitin-protein ligase targeting the telomerase catalytic subunit (TERT) for proteasome processing. It regulates the ubiquitination and degradation of peroxisome-proliferator-activated receptor gamma (PPARgamma), a nuclear receptor that is linked to obesity and metabolic diseases. It also mediates the posttranslational regulation of p14ARF, and thus potentially regulates cellular senescence and tumorigenesis in gastric cancer. Moreover, MKRN1 functions as a differentially negative regulator of p53 and p21, and controls cell cycle arrest and apoptosis. It induces degradation of West Nile virus (WNV) capsid protein to protect cells from WNV. It is a RNA-binding protein involved in the modulation of cellular stress and apoptosis. It predominantly associates with proteins involved in mRNA metabolism including regulators of mRNA turnover, transport, and/or translation, and acts as a component of a ribonucleoprotein complex in embryonic stem cells (ESCs) that is recruited to stress granules upon exposure to environmental stress. MKRN1 interacts with poly(A)-binding protein (PABP), a key component of different ribonucleoprotein complexes, in an RNA-independent manner, and stimulates translation in nerve cells. In addition, MKRN1 is a novel SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen of esophageal squamous cell carcinoma (SCC). It may be involved in carcinogenesis of the well-differentiated type of tumors possibly via ubiquitination of filamin A interacting protein 1 (L-FILIP). Human MKRN1 contains three N-terminal C3H1-type zinc fingers, a motif rich in Cys and His residues (CH), a C3HC4-type RING-HC finger, and another C3H1-type zinc finger at the C-terminus. MKRN3, also known as makorin RING finger protein 3, RING finger protein 63 (RNF63), or zinc finger protein 127 (ZNF127), is a therian mammal-specific retrocopy of MKRN1. It acts as a putative E3 ubiquitin-protein ligase involved in ubiquitination and cell signaling. MKRN3 shows a potential inhibitory effect on hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Its defects represent the most frequent known genetic cause of familial central precocious puberty (CPP). In contrast to human MKRN1, human MKRN3 lacks the second C3H1-type zinc finger at the N-terminal region. The RING-HC finger of mammalian MKRN4 shows high sequence similarity with that of MKRN3, and is also included in this model.

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gi 646397358  84 DDLCSICFE--------KPITYGLLVGCSHVFCINCIREWRapankSTEVVSSGVIKKCPYCRVEA 141
Cdd:cd16730    1 DKVCGICMEvvyekanpSERRFGILSNCNHTYCLKCIRKWR-----SAKQFESKIIKSCPECRITS 61

RING finger, HC subclass, found in makorin-2 (MKRN2) and similar proteins; MKRN2, also known as makorin RING finger protein 2, RING finger protein 62 (RNF62), or HSPC070, is a putative ribonucleoprotein that acts as a neurogenesis inhibitor acting upstream of glycogen synthase kinase-3beta (GSK-3beta) in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. It also functions in promoting cell proliferation of primary CD34+ progenitor cells and K562 cells, indicating its possible involvement in normal and malignant hematopoiesis. Mammalian MKRN2 contains three N-terminal C3H1-type zinc fingers, a motif rich in Cys and His residues (CH), a C3HC4-type RING-HC finger, and another C3H1-type zinc finger at the C-terminus. The third C3H1-type zinc finger, the CH motif, as well as the RING zinc finger are necessary for its anti-neurogenic activity.

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gi 646397358  84 DDLCSIC----FEKPIT----YGLLVGCSHVFCINCIREWRApanksTEVVSSGVIKKCPYCR 138
Cdd:cd16731    1 DKVCSICmevvYEKASAserrFGILSNCNHTYCLSCIRQWRC-----AKQFENPIIKSCPECR 58

RING finger, HC subclass, found in topoisomerase I-binding arginine/serine-rich protein (Topors) and similar proteins; Topors, also known as topoisomerase I-binding RING finger protein, tumor suppressor p53- binding protein 3, or p53-binding protein 3 (p53BP3), is a ubiquitously expressed nuclear E3 ubiquitin-protein ligase that can ligate both ubiquitin and small ubiquitin-like modifier (SUMO) to substrate proteins in the nucleus. It contains an N-terminal C3HC4-type RING-HC finger which ligates ubiquitin to its target proteins including DNA topoisomerase I, p53, NKX3.1, H2AX, and the AAV-2 Rep78/68 proteins. As a RING-dependent E3 ubiquitin ligase, Topors works with the E2 enzymes UbcH5a, UbcH5c, and UbcH6, but not with UbcH7, CDC34, or UbcH2b. Topors acts as a tumor suppressor in various malignancies. It regulates p53 modification, suggesting it may be responsible for astrocyte elevated gene-1 (AEG-1, also known as metadherin, or LYRIC) ubiquitin modification. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. It also functions as a negative regulator of the prostate tumor suppressor NKX3.1. Moreover, Topors is associated with promyelocytic leukemia nuclear bodies, and may be involved in the cellular response to camptothecin. It also plays a key role in the turnover of H2AX protein, discriminating the type of DNA damaging stress. Furthermore, Topors is a cilia-centrosomal protein associated with autosomal dominant retinal degeneration. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa (adRP).

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                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 646397358  84 DDLCSICFEKPITY-GLLVGCSHVFCINCIREWrapankstevvsSGVIKKCPYCR 138
Cdd:cd16574    1 DSSCPICLDRFENEkAFLDGCFHAFCFTCILEW------------SKVKNECPLCK 44

RING finger, HC subclass, found in RING finger protein 8 (RNF8) and similar proteins; RNF8 is a telomere-associated E3 ubiquitin-protein ligase that plays an important role in DNA double-strand break (DSB) repair via histone ubiquitination. It is localized in the nucleus and interacts with class III E2s (UBE2E2, UbcH6, and UBE2E3), but not with other E2s (UbcH5, UbcH7, UbcH10, hCdc34, and hBendless). It recruits UBC13 for lysine 63-based self polyubiquitylation. Its deficiency causes neuronal pathology and cognitive decline, and its loss results in neuron degeneration. RNF8, together with RNF168, catalyzes a series of ubiquitylation events on substrates such as H2A and H2AX, with the H2AK13/15 ubiquitylation being particularly important for recruitment of repair factors p53-binding protein 1 (53BP1) or the RAP80-BRCA1 complex to sites of DSBs. RNF8 mediates the ubiquitination of gammaH2AX, and recruits 53BP1 and BRCA1 to DNA damage sites which promotes DNA damage response (DDR) and inhibits chromosomal instability. Moreover, RNF8 interacts with retinoid X receptor alpha (RXR alpha) and enhances its transcription-stimulating activity. It also regulates the rate of exit from mitosis and cytokinesis. RNF8 contains an N-terminal forkhead-associated (FHA) domain and a C-terminal C3HC4-type RING-HC finger.

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                 ....*....|....*....|....*....|....*....|....*....|..
gi 646397358  87 CSICFEKPItYGLLVGCSHVFCINCIREWRApankstevvssgVIKKCPYCR 138
Cdd:cd16535    4 CSICSELFI-EAVTLNCSHSFCSYCITEWMK------------RKKECPICR 42

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

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                  ....*....|....*....|....*....
gi 646397358   87 CSICFEKPITYGLLVGCSHVFCINCIREW 115
Cdd:pfam00097   1 CPICLEEPKDPVTLLPCGHLFCSKCIRSW 29

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

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gi 646397358    87 CSICFEKPITYGLLVGCSHVFCINCIREW 115
Cdd:smart00184   1 CPICLEEYLKDPVILPCGHTFCRSCIRKW 29

Zinc finger domain; This is a zinc finger domain found in Zinc finger CCCH-type with G patch domain-containing proteins such as ZIP. Functional studies indicate that ZIP specifically targets EGFR and represses its transcription, and that the zinc finger and the coiled-coil domains are central to that process.

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gi 646397358   53 CIYYAQGYCRRGSQCWFKH 71
Cdd:pfam18345   1 CKFFLKGRCRYGDKCRFAH 19

RING finger, HC subclass, found in midline-1 (MID1) and similar proteins; MID1, also known as midin, midline 1 RING finger protein, putative transcription factor XPRF, RING finger protein 59 (RNF59), or tripartite motif-containing protein 18 (TRIM18), is a microtubule-associated E3 ubiquitin-protein ligase implicated in epithelial-mesenchymal differentiation, cell migration and adhesion, and programmed cell death along specific regions of the ventral midline during embryogenesis. It monoubiquinates the alpha4 subunit of protein phosphatase 2A (PP2A), promoting proteosomal degradation of the catalytic subunit of PP2A (PP2Ac) and preventing the A and B subunits from forming an active complex. It promotes allergen and rhinovirus-induced asthma through the inhibition of PP2A activity. It is strongly upregulated in cytotoxic lymphocytes (CTLs) and directs lytic granule exocytosis and cytotoxicity of killer T cells. Loss-of-function mutations in MID1 lead to the human X-linked Opitz G/BBB (XLOS) syndrome characterized by defective midline development during embryogenesis. MID1 belongs to the C-I subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a COS (carboxyl-terminal subgroup one signature) box, a fibronectin type III (FN3) domain, and a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. MID1 hetero-dimerizes in vitro with its paralog MID2.

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gi 646397358  83 SDDLCSIC---FEKPitygLLVGCSHVFCINCIREWRAPANKSTEVVSSGVIKKCPYCR 138
Cdd:cd16753    4 SELTCPIClelFEDP----LLLPCAHSLCFNCAHRILVSHCASNESVESITAFQCPTCR 58