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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 19114645 190 PECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHPYFSCFICR 236
Cdd:cd16458   1 PDCSICLFPVLPCQALFVSPCAHSWHFKCIRPLLEASYPQFSCPNCR 47

RING finger, H2 subclass, found in defective in mitotic arrest proteins (Dmap) and similar proteins; This subfamily includes Schizosaccharomyces pombe protein Dma1 (SpDma1p), Saccharomyces cerevisiae proteins Dma1 (ScDma1p) and Dma2 (ScDma2p), and their homologs from fungi. SpDma1p was originally isolated as a multicopy suppressor of the temperature-sensitive growth phenotype caused by cdc16 mutations. It functions to prevent mitotic exit and cytokinesis during spindle checkpoint arrest by inhibiting septation initiation network (SIN) signaling. ScDma1p and ScDma2p, also known as checkpoint forkhead associated with RING domains-containing protein 1 and 2 respectively, seem to be functionally redundant. They are involved in proper septin ring positioning and cytokinesis. The simultaneous lack of Dma1 and Dma2 leads to spindle mispositioning and defects in the spindle position checkpoint. All members of this family contain a forkhead-associated (FHA) domain and a C3H2C3-type RING-H2 finger, the latter suggesting they may possess E3 ubiquitin-ligase activities.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 19114645 190 PECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHPYFSCFICR 236
Cdd:cd16458   1 PDCSICLFPVLPCQALFVSPCAHSWHFKCIRPLLEASYPQFSCPNCR 47

FHA domain; The FHA (Forkhead-associated) domain is a phosphopeptide binding motif.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 19114645    60 IYIGRyteryngGDVSAIVFRSKVVSRRHAQIFYENN-TWYIQDMGSSSGTFLNHVRLSPpsktsKPYPISNNDILQL 136
Cdd:pfam00498   1 VTIGR-------SPDCDIVLDDPSVSRRHAEIRYDGGgRFYLEDLGSTNGTFVNGQRLGP-----EPVRLKDGDVIRL 66

Forkhead associated domain; Found in eukaryotic and prokaryotic proteins. Putative nuclear signalling domain.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 19114645     62 IGRYTERYNggdvsaIVFRSKVVSRRHAQIFYENNT-WYIQDMGSSSGTFLNHVRL 116
Cdd:smart00240   3 IGRSSEDCD------IQLDGPSISRRHAVIVYDGGGrFYLIDLGSTNGTFVNGKRI 52

forkhead associated (FHA) domain found in sarcolemmal membrane-associated protein (SLMAP) and similar proteins; SLMAP, also called sarcolemmal-associated protein (SLAP), is a tail-anchored protein involved in fundamental cellular processes, such as myoblast fusion, cell cycle progression, and chromosomal inheritance. It is a cardiac membrane protein that plays an important role in E-C coupling and the adrenergic response of the heart. Overexpression of the SLMAP gene has been associated with diabetes and endothelial dysfunction of macro- and micro-blood vessels. SLMAP contains an N-terminal FHA domain, which is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19114645  37 PNAHSFsfdplvrywNRKQNNL--PIYIGRYTERYNGGDVSAIvFRSKVVSRRHAQIFYENNTWYIQDMGSSSGTFLNHV 114
Cdd:cd22679  10 PNSHPF---------QERHIVLdePVKIGRSVARARPAANNAI-FDCKVLSRNHALLWYDDGKFYLQDTKSSNGTFVNNQ 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 19114645 115 RLSPPSKTSKPYPISNNDILQLGAD-YRGGHEVNYRCVRARVEL 157
Cdd:cd22679  80 RLSKGSEESEPRELHSGDIVQFGVDvVENSRKVTHGCIVATVTL 123

Forkhead associated (FHA) domain, binds pSer, pThr, pTyr [Signal transduction mechanisms];

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 19114645  59 PIYIGRYTErynggdvSAIVFRSKVVSRRHAQIFYENNTWYIQDMGSSSGTFLNHVRLsppsktSKPYPISNNDILQLG 137
Cdd:COG1716  22 PLTIGRAPD-------NDIVLDDPTVSRRHARIRRDGGGWVLEDLGSTNGTFVNGQRV------TEPAPLRDGDVIRLG 87

FHA domain; The FHA (Forkhead-associated) domain is a phosphopeptide binding motif.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 19114645    60 IYIGRyteryngGDVSAIVFRSKVVSRRHAQIFYENN-TWYIQDMGSSSGTFLNHVRLSPpsktsKPYPISNNDILQL 136
Cdd:pfam00498   1 VTIGR-------SPDCDIVLDDPSVSRRHAEIRYDGGgRFYLEDLGSTNGTFVNGQRLGP-----EPVRLKDGDVIRL 66

forkhead associated (FHA) domain found in angiogenic factor with G patch and FHA domains 1 (AGGF1) and similar proteins; AGGF1, also called angiogenic factor VG5Q, or G patch domain-containing protein 7 (GPATC7), or vasculogenesis gene on 5q protein, is an angiogenic factor involved in vascular development, angiogenesis, specification of hemangioblasts, and differentiation of veins. It promotes angiogenesis and the proliferation of endothelial cells. It inhibits inflammatory effect and preserve vascular integrity in non-nervous system diseases. Mutated AGGF1 causes susceptibility to Klippel-Trenaunay syndrome, a vascular disorder. Increased AGGF1 expression is associated with tumor angiogenesis. The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 19114645  84 VSRRHAQIFYENN--TWYIQDMGSSSGTFLNHVRLSPPSKTSKPYPISNNDILQLG 137
Cdd:cd22686  47 VSKFHAEIYYDDDeqSYTIVDLGSQNGTYLNGVRISQPKEKSDPYPLTHGDELKIG 102

forkhead associated (FHA) domain found in Arabidopsis thaliana protein phosphatase 2C 70 (AtPP2C70) and similar proteins; AtPP2C70, also called kinase-associated protein phosphatase, or protein ROOT ATTENUATED GROWTH 1, dephosphorylates the serine/threonine receptor-like kinase RLK5. It may function as a signaling component in a pathway involving RLK5. It acts as a negative regulator of the CLAVATA1 signaling in plant development by binding and dephosphorylating CLAVATA1. It is also a component of a signaling pathway which mediates adaptation to NaCl stress. It contains an FHA domain, which is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19114645  57 NLPIYIGRYTERynggdvsAIVFRSKVVSRRHAQIFYeNNT---WYIQDMGSSSGTFLNHVRLSPPsktSKPYPISNNDI 133
Cdd:cd22678  22 RLPLTIGRIQRG-------DIALKDDEVSGKHARIEW-NSTgskWELVDLGSLNGTLVNGESISPN---GRPVVLSSGDV 90

                ....
gi 19114645 134 LQLG 137
Cdd:cd22678  91 ITLG 94

forkhead associated (FHA) domain 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. Specially, 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 FHA domain, which is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 19114645  81 SKVVSRRHAQI-FYENNTWYIQDMGSSSGTFLNHVRLSPpsktSKPYPISNNDILQLGADYRGGHEVNYRC 150
Cdd:cd22663  40 PLMISRNHCVLkKNDEGQWTIKDNKSLNGVWVNGERIEP----LKPYPLNEGDLIQLGVPPENKEPAEYVF 106

forkhead associated (FHA) domain found in protein phosphatase 1 regulatory inhibitor subunit 8 (PPP1R8) and similar proteins; PPP1R8, also called nuclear inhibitor of protein phosphatase 1 (NIPP-1), is an inhibitor subunit of the major nuclear protein phosphatase-1 (PP-1). It has RNA-binding activity but does not cleave RNA and may target PP-1 to RNA-associated substrates. It may also be involved in pre-mRNA splicing and binds DNA and might act as a transcriptional repressor. PPP1R8 seems to be required for cell proliferation. PPP1R8 contains an FHA domain that mediates interactions with threonine-phosphorylated maternal embryonic leucine zipper kinase (MELK). The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 19114645  84 VSRRHAQIFYE--NNTWYIQDMGSSSGTFLNHVRLSPpsktSKPYPISNNDILQLGADYR 141
Cdd:cd22674  47 CSRVHAALVYHkhLNRVFLIDLGSTHGTFVGGIRLEP----HKPQQLPIDSTLRFGASTR 102

forkhead associated (FHA) domain found in Saccharomyces cerevisiae fork head protein homolog 1 (FKH1), 2 (FKH2) and similar proteins; This family includes FKH1 and FKH2, as well as pre-rRNA-processing protein FHL1. FKH1 and FKH2 are forkhead transcription factors that regulate the expression of the CLB2 cluster of genes during the G2/M phase of the mitotic cell cycle. The CLB2 cluster of genes includes mitotic regulators such as CLB1, CLB2, CDC5 and CDC20, as well as SWI5 and ACE2. FKH1 and FKH2 are involved in HMRa silencing. They associate with the coding regions of active genes and influence, in opposing ways, transcriptional elongation and termination, and coordinate early transcription elongation and pre-mRNA processing. Both FKH1 and FKH2 play a role as regulators of lifespan in collaboration with the anaphase-promoting complex (APC), likely through combined regulation of stress response, genomic stability, and cell cycle regulation. They also function in controlling yeast cell morphology by preventing pseudohyphal growth and act as rate-limiting replication origin activators via their interaction with the origin recognition complex (ORC). FHL1 is a forkhead protein that controls the pre-rRNA processing machinery in conjunction with IFH1. It might act as a transcriptional regulator of genes specifically involved in that process. IFH1 convert FHL1 from a repressor to an activator. This family also includes AtFHA1 and AtFHA2, which may play a role in the control of plant organ development. AtFHA2 is specifically involved in the regulation of stamen development. The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19114645  50 YWNRKqnnLPIYIGRYTERYNGGDVSA--IVFR-SKVVSRRHAQIFY--ENNTWYIQDMGsSSGTFLNHVRLSPpskTSK 124
Cdd:cd22701  12 YYVQK---LEVVLGRNSKNSSSTAADSvdIDLGpSKKISRRHARIFYdfTTQCFELSVLG-RNGVKVDGILVKP---GSP 84

                        90
                ....*....|...
gi 19114645 125 PYPISNNDILQLG 137
Cdd:cd22701  85 PVPLRSGSLIQIG 97

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 19114645   190 PECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyfSCFICR 236
Cdd:pfam13639   1 DECPICLEEFEEGDKVVVLPCGHHFHRECLDKWLRSSN---TCPLCR 44

forkhead associated (FHA) domain found in Mycobacterium tuberculosis FHA domain-containing protein FhaA and similar proteins; FhaA regulates cell growth and peptidoglycan synthesis by binding to MviN. It may inhibit the late stages of peptidoglycan synthesis. It contains an FHA domain, which is a small phosphopeptide recognition module.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 19114645  83 VVSRRHAQIFYENNTWYIQDMGSSSGTFLNHVRLSPpsktskPYPISNNDILQLG 137
Cdd:cd22668  36 GVSRRHAEIRWDGQVAHLTDLGSTNGTTVNNAPVTP------EWRLADGDVITLG 84

forkhead associated (FHA) domain found in kanadaptin and similar proteins; Kanadaptin, also called human lung cancer oncogene 3 protein (HLC-3), kidney anion exchanger adapter protein, or solute carrier family 4 anion exchanger member 1 adapter protein (SLC4A1AP), is a nuclear protein widely expressed in mammalian tissues. It was originally isolated as a kidney Cl-/HCO3- anion exchanger 1 (kAE1)-binding protein. It is a highly mobile nucleocytoplasmic shuttling and multilocalizing protein. Its role in mammalian cells remains unclear. It contains an FHA domain, which is a small phosphopeptide recognition module.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 19114645  84 VSRRHAQIFY------ENNTWYIQDMGSSSGTFLNHVRLSPpsktSKPYPISNNDILQLGADYR 141
Cdd:cd22677  41 ISRYHAVLQYrgdaddHDGGFYLYDLGSTHGTFLNKQRIPP----KQYYRLRVGHVLKFGGSTR 100

H2 subclass of RING (RING-H2) fingers 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 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). This family corresponds to the H2 subclass of RING (RING-H2) finger proteins that are characterized by containing C3H2C3-type canonical RING-H2 fingers or noncanonical RING-H2 finger variants, including C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type modified RING-H2 fingers. The canonical RING-H2 finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-H-X2-C-X(4-48)-C-X2-C, X is any amino acid and the number of X residues varies in different fingers. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-H2 finger 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 serves as a scaffold 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 19114645 192 CCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyFSCFICR 236
Cdd:cd16448   1 CVICLEEFEEGDVVRLLPCGHVFHLACILRWLESGN--NTCPLCR 43

Inner membrane component of T3SS, cytoplasmic domain; Yop-YscD-cpl is the cytoplasmic domain of Yop proteins like YscD from Proteobacteria. YscD forms part of the inner membrane component of the bacterial type III secretion injectosome apparatus.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 19114645    60 IYIGRyteryngGDVSAIVFRSKVVSRRHAQIFYENNTWYIQDMGSSSGTFLNHVRLSPPSKTSKPypisnNDILQLG 137
Cdd:pfam16697  19 YRIGS-------DPDCDIVLSDKEVSRVHLKLEVDDEGWRLDDLGSGNGTLVNGQRVTELGIALRP-----GDRIELG 84

forkhead associated (FHA) domain found in Saccharomyces cerevisiae DNA damage response protein kinase DUN1 and similar proteins; DUN1 is a protein kinase that controls the DNA damage response in yeast. It phosphorylates SML1 on serine residues and cooperates with the PAN deadenylation complex in the regulation of RAD5 mRNA levels and cell survival in response to replicational stress. It contains an FHA domain, which is a small phosphopeptide recognition module.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 19114645  77 IVFRSKVVSRRHAQIFYENNTWYIQDMGSSSGTFLNHVRLSppsktSKPYPISNNDILQLG 137
Cdd:cd22683  33 LVLSDPSISRFHAELRLEQNGINVIDNNSANGTFINGKRIK-----GKTYILKNGDIIVFG 88

RING finger, H2 subclass, found in Arabidopsis thaliana protein WAV3 homolog 2 (WAVH2) and similar proteins; WAVH2, also known as RING-type E3 ubiquitin transferase WAVH2, is a probable E3 ubiquitin-protein ligase involved in the regulation of root growth. It acts as a positive regulator of root gravitropism. WAVH2 contains a C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 19114645 191 ECCICLMPVLPCQ--ALFVAPCSHSYHYKCIRPtlNESHPYFSCFICR 236
Cdd:cd23114   6 ECSICLETMKPGSghAIFTAECSHSFHFECIAG--NVRHGNLRCPVCR 51

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)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 19114645    192 CCICLMPvlPCQALFVAPCSHSYHYKCIRPTLNESHpyFSCFIC 235
Cdd:smart00184   1 CPICLEE--YLKDPVILPCGHTFCRSCIRKWLESGN--NTCPIC 40

forkhead associated (FHA) domain found in Saccharomyces cerevisiae vacuolar protein sorting-associated protein 64 (VPS64) and similar proteins; This subfamily includes VPS64 (also called factor arrest protein 9 or FAR9) and factor arrest protein 10 (FAR10), which participate in the control of the re-entry into the cell cycle following pheromone treatment. VPS64 is also involved in vacuolar protein sorting. The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19114645  79 FRSKVVSRRHAQIFYENNTW--YIQDMGSSSGTFLNHVRLSppsktSKPYPISNNDILQLGADYRGghEVNYRCVRARVE 156
Cdd:cd22695  60 FDSRVLSRNHACLSCDPTTGkvYIRDLKSSNGTFVNGQKIR-----QNDVELKVGDEVDLGTDIDS--KIEHRKISAYVE 132

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

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 19114645 191 ECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyfSCFICR 236
Cdd:cd16454   1 TCAICLEEFKEGEKVRVLPCNHLFHKDCIDPWLEQHN---TCPLCR 43

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

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 19114645 190 PECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyfSCFICR 236
Cdd:cd16472   3 TQCVVCMCDYEKRQLLRVLPCSHEFHAKCIDKWLKTNR---TCPICR 46

RING finger, H2 subclass, found in RING finger protein 13 (RNF13) and similar proteins; RNF13 is a widely expressed membrane-associated E3 ubiquitin-protein ligase that is functionally significant in the regulation of cancer development, muscle cell growth, and neuronal development. Its expression is developmentally regulated during myogenesis and is upregulated in various tumors. RNF13 negatively regulates cell proliferation through its E3 ligase activity. It functions as an important regulator of inositol-requiring transmembrane kinase/endonuclease IRE1alpha, mediating endoplasmic reticulum (ER) stress-induced apoptosis through the activation of the IRE1alpha-TRAF2-JNK signaling pathway. Moreover, RNF13 is involved in the regulation of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex via the ubiquitination of snapin, a SNAP25-interacting protein, which thereby controls synaptic function. In addition, RNF13 participates in regulating the function of satellite cells by modulating cytokine composition. RNF13 is evolutionarily conserved among many metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 19114645 192 CCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHPyfSCFICRK 237
Cdd:cd16796  11 CAICLDEYEEGDKLRILPCSHAYHCKCVDPWLTKTKK--TCPVCKQ 54

forkhead associated (FHA) domain found in centrosomal protein of 170 kDa (Cep170) and similar proteins; Cep170, also called Cep170A, KARP-1-binding protein, or KARP1-binding protein, is a protein that localizes to centrosomes as well as spindle microtubules and plays a role in microtubule organization and microtubule assembly. It is required for centriole subdistal appendage assembly. Cep170 is phosphorylated during M phase and interacts with Polo-like kinase 1 (Plk1). The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19114645  60 IYIGRyterynggDVSAIVFRSKVVSRRHAQIFYENNT--WYIQDMGSSSGTFLNHVRLsppsktskpyPISNNDILQLG 137
Cdd:cd22724  23 IFVGR--------DDCELMLQSRSVDKQHAVINYDASTdeHKVKDLGSLNGTFVNDVRI----------PEQTYITLKLD 84

                        90
                ....*....|
gi 19114645 138 ADYRGGHEVN 147
Cdd:cd22724  85 DKLRFGYDTN 94

RING finger, H2 subclass, found in zinc/RING finger protein 3 (ZNRF3) and similar proteins; ZNRF3, also known as RING finger protein 203 (RNF203), is a homolog of Ring finger protein 43 (RNF43). It is a transmembrane E3 ubiquitin-protein ligase that is associated with the Wnt receptor complex, and negatively regulates Wnt signaling by promoting the turnover of frizzled and lipoprotein receptor-related protein LRP6 in an R-spondin-sensitive manner. It inhibits gastric cancer cell growth and promotes cell apoptosis by affecting the Wnt/beta-catenin/TCF signaling pathway. ZNRF3 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger followed by a long C-terminal region.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 19114645 191 ECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyfSCFICR 236
Cdd:cd16799   1 DCAICLEKYIDGEELRVIPCTHRFHKKCVDPWLLQHH---TCPHCR 43

RING finger, H2 subclass, found in RING finger protein 11 (RNF11) and similar proteins; RNF11 is an E3 ubiquitin-protein ligase that acts both as an adaptor and a modulator of itch-mediated control of ubiquitination events underlying membrane traffic. It acts downstream of an enzymatic cascade for the ubiquitination of specific substrates. It is also a molecular adaptor of homologous to E6-associated protein C-terminus (HECT)-type ligases. RNF11 has been implicated in the regulation of several signaling pathways. It enhances transforming growth factor receptor (TGFR) signaling by both abrogating Smurf2-mediated receptor ubiquitination and by promoting the Smurf2-mediated degradation of AMSH (associated molecule with the SH3 domain of STAM), a de-ubiquitinating enzyme that enhances TGF-beta signaling and epidermal growth factor receptor (EGFR) endosomal recycling. It also acts directly on Smad4 to enhance Smad4 function, and plays a role in prolonged TGF-beta signaling. RNF11 also functions as a critical component of the A20 ubiquitin-editing protein complex that negatively regulates tumor necrosis factor (TNF)-mediated nuclear factor (NF)-kappaB activation. It interacts with Smad anchor for receptor activation (SARA) and the endosomal sorting complex required for transport (ESCRT)-0 complex, thus participating in the regulation of lysosomal degradation of EGFR. RNF11 acts as a novel GGA cargo actively participating in regulating the ubiquitination of the GGA protein family. RNF11 functions together with TAX1BP1 to target TANK-binding kinase 1 (TBK1)/IkappaB kinase IKKi, and further restricts antiviral signaling and type I interferon (IFN)-beta production. RNF11 contains an N-terminal PPPY motif that binds WW domain-containing proteins such as AIP4/itch, Nedd4 and Smurf1/2 (SMAD-specific E3 ubiquitin-protein ligase 1/2), and a C-terminal C3H2C3-type RING-H2 finger that functions as a scaffold for the coordinated transfer of ubiquitin to substrate proteins together with the E2 enzymes UbcH527 and Ubc13.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 19114645 191 ECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNEShpyFSCFIC 235
Cdd:cd16468   1 ECVICMADFVVGDPIRYLPCMHIYHVDCIDDWLMRS---FTCPSC 42

RING finger, H2 subclass, found in Saccharomyces cerevisiae alcohol-sensitive RING finger protein 1 (ASR1) and similar proteins; ASR1 is required for tolerance to alcohol. It signals alcohol stress to the nucleus. ASR1 contains a C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 19114645 190 PECCICLMPvLPCQALFVAPCSHSYHYKCIRPTLNeSHPYFSCFICRKY 238
Cdd:cd23120   2 EECPICLEE-MNSGTGYLADCGHEFHLTCIREWHN-KSGNLDCPICRVE 48

forkhead associated (FHA) domain found in Saccharomyces cerevisiae pre-mRNA leakage protein 1 (PML1) and similar proteins; PML1 is an FHA domain-containing protein required for efficient splicing and pre-mRNA nuclear retention. It is a component of the pre-mRNA retention and splicing (RES) complex composed of at least BUD13, IST3, and PML1. It contains an FHA domain, which is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19114645  62 IGRYTERYNGGDVSAIVFRSKVVSRRHAQI-FYENN---TWYIQDMGSSSGTFLNHVRLsPPSKTSKpypISNNDILQLG 137
Cdd:cd22681  44 IGREKGESTEIVVADIGIPEETCSKQHCVIqFRNVKgilKPYIMDLDSSNGTCLNDNVI-PSSRYVE---LRSGDVITFS 119

                ..
gi 19114645 138 AD 139
Cdd:cd22681 120 KS 121

RING finger, H2 subclass, found in RING finger protein 12 (RNF12) and similar proteins; RNF12, also known as LIM domain-interacting RING finger protein or RING finger LIM domain-binding protein (R-LIM), is an E3 ubiquitin-protein ligase encoded by gene RLIM that is crucial for normal embryonic development in some species and for normal X inactivation in mice. It thus functions as a major sex-specific epigenetic regulator of female mouse nurturing tissues. RNF12 is widely expressed during embryogenesis, and mainly localizes to the cell nucleus, where it regulates the levels of many proteins, including CLIM, LMO, HDAC2, TRF1, SMAD7, and REX1, by proteasomal degradation. Its functional activity is regulated by phosphorylation-dependent nucleocytoplasmic shuttling. It is negatively regulated by pluripotency factors in embryonic stem cells. p53 represses its transcription through Sp1. RNF12 is the primary factor responsible for X chromosome inactivation (XCI) in female placental mammals. It is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI. It also targets REX1, an inhibitor of XCI, for proteasomal degradation. RNF12 also acts as a co-regulator for a range of transcription factors, particularly those containing a LIM homeodomain, and modulates the formation of transcriptional multiprotein complexes. It is a negative regulator of Smad7, which in turn negatively regulates the signaling of type I receptors from the transforming growth factor beta (TGF-beta) superfamily. In addition, paternal RNF12 is a critical survival factor for milk-producing alveolar cells. RNF12 contains an nuclear localization signal (NLS) and a C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 19114645 192 CCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyfSCFICRK 237
Cdd:cd16674   3 CSVCITEYTEGNKLRKLPCSHEYHVHCIDRWLSENS---TCPICRR 45

RING finger, H2 subclass, found in RING finger protein 13 (RNF13), RING finger protein 167 (RNF167), and similar proteins; This subfamily includes RING finger protein 13 (RNF13), RING finger protein 167 (RNF167), Zinc/RING finger protein 4 (ZNRF4), and similar proteins, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane domain (TM), and a C-terminal C3H2C3-type RING-H2 finger followed by a putative PEST sequence. RNF13 is a widely expressed membrane-associated E3 ubiquitin-protein ligase that functions in the regulation of cancer development, muscle cell growth, and neuronal development. Its expression is developmentally regulated during myogenesis and is upregulated in various tumors. RNF13 negatively regulates cell proliferation through its E3 ligase activity. RNF167, also known as RING105, is an endosomal/lysosomal E3 ubiquitin-protein ligase involved in the ubiquitination of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). It acts as an endosomal membrane protein which ubiquitylates vesicle-associated membrane protein 3 (VAMP3) and regulates endosomal trafficking. Moreover, RNF167 plays a role in the regulation of TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA, also known as ORCTL2/IMPT1/BWR1A/SLC22A1L), which can function in concert with the ubiquitin-conjugating enzyme UbcH6. ZNRF4, also known as RING finger protein 204 (RNF204), or Nixin, is an endoplasmic reticulum (ER) membrane-anchored ubiquitin ligase that physically interacts with the ER-localized chaperone calnexin in a glycosylation-independent manner, inducing calnexin ubiquitination, and p97-dependent degradation. The murine protein sperizin (spermatid-specific ring zinc finger) is a homolog of human ZNRF4. It is specifically expressed in Haploid germ cells and is involved in spermatogenesis.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 19114645 192 CCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHPyfSCFICRK 237
Cdd:cd16665   3 CAICLDDYEEGDKLRILPCSHAYHCKCIDPWLTKNKR--TCPVCKR 46

forkhead associated (FHA) domain found in proliferation marker protein Ki-67 and similar proteins; Ki-67, also called antigen identified by monoclonal antibody Ki-67, antigen KI-67, or antigen Ki67, acts as a biological surfactant to disperse mitotic chromosomes. It is required to maintain individual mitotic chromosomes dispersed in the cytoplasm following nuclear envelope disassembly. Ki-67 binds DNA with a preference for supercoiled DNA and AT-rich DNA. It may also play a role in chromatin organization. Ki-67 contains an FHA domain at its N-terminus. The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 19114645  84 VSRRHAQIFY-ENNTWYIQDMGSSSGTFLNhvrlspPSKTSKPYPISNNDILQLG 137
Cdd:cd22673  40 VSREHCRIEVdENGKAYLENLSTTNPTLVN------GKAIEKSAELKDGDVITIG 88

RING finger, HC subclass, found in RING finger protein 141 (RNF141) and similar proteins; RNF141, also known as zinc finger protein 230 (ZNF230), is a RING finger protein present primarily in the nuclei of spermatogonia, the acrosome, and the tail of spermatozoa. It may have a broad function during early development of vertebrates. It plays an important role in spermatogenesis, including spermatogenic cell proliferation and sperm maturation, as well as motility and fertilization. It also exhibits DNA binding activity. RNF141/ZNF230 gene mutations may be associated with azoospermia. RNF141 contains a C3HC4-type RING finger domain that may function as an activator module in transcription.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 19114645 191 ECCICLmpvlPCQALFVAPCSHSYHYKCIRpTLNESHPyfSCFICR 236
Cdd:cd16545   2 ECCICM----DRKADLILPCAHSYCQKCID-KWSDRHR--TCPICR 40

forkhead associated (FHA) domain found in Mycobacterium tuberculosis glycogen accumulation regulator GarA and similar proteins; GarA is an FHA domain-containing protein involved in the regulation of glutamate metabolism. It acts as a phosphorylation-dependent ON/OFF molecular switch that modulates the activities of KGD, GDH and GltB. Its FHA domain has dual specificity. It binds to both phosphorylated upstream partners, such as the kinases PknB and PknG, and nonphosphorylated downstream partners, such as the 2-oxoglutarate decarboxylase KGD. The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 19114645  75 SAIVFRSKVVSRRHAQIFYENNTWYIQDMGSSSGTFLNHvrlsPPSKTSKpypISNNDILQLG 137
Cdd:cd22720  34 SDIFLDDVTVSRRHAEFRLENNEFNVVDVGSLNGTYVNR----EPVDSAV---LANGDEVQIG 89

RING finger, H2 subclass, found in RING finger protein 44 (RNF44) and similar proteins; RNF44 is an uncharacterized RING finger protein that shows high sequence similarity with RNF38, which is a nuclear E3 ubiquitin protein ligase that plays a role in regulating p53. RNF44 contains a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), and a C3H2C2-type RING-H2 finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 19114645 184 SSESGPPECCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyfSCFICR 236
Cdd:cd16680   2 NHQSEQTLCVVCFSDFESRQLLRVLPCNHEFHTKCVDKWLKTNR---TCPICR 51

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

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 19114645 192 CCICLMPVLPCQALFVAPCSHSYHYKCIRPTLNESHpyfSCFICR 236
Cdd:cd16668   2 CAVCIEPYKPSDVIRILPCKHIFHKSCVDPWLLEHR---TCPMCK 43