Cysteine rich domain with multizinc binding regions; This is a cysteine rich domain which contains four zinc-binding regions (binding five zinc ions). Family members include human CHFR which interacts with Poly(ADP-ribose) (PAR) through a 20-amino acid PAR binding zinc finger region (PBZ) found at the C-terminal end of this cysteine-rich domain (i.e. the 4th region towards the C-terminal). CHFR lacking PBZ does not co-localize with nuclear PAR foci in interphase cells and cannot rescue antephase checkpoint function despite retaining autoubiquitination activity. Hence it has been suggested that the CHFR-PAR interaction is an important part of the antephase checkpoint and could form part of the checkpoint sensor for cellular stress and microtubule poisons or be required for proper localization of CHFR. The PBZ region of CHFR contains two adenine binding sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591   256 CPQCVANIGGYRCEHHGAHLQCHLCQGMMPFRANLQVPLHCKGCDRPFCGAYWssenvtQGVSGPVCVReTFRPISERTI 335
Cdd:pfam17979   1 CPQCGTAIGGFQCPPQTQHLQCTCCGGMMPDRRDAGVPQQCLLCKRPFCGLYW------GGCPRAGCQG-CLKPFSENLI 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591   336 TRIPFITHEMNRHEQDITQRCIAHMEKTVPDVVAEWLRLFNNREIDRSRMPLNHAET-ITASTHVCNDCYDKLVGFLLYW 414
Cdd:pfam17979  74 SKIPDNVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIDRTRKPLNLSDYiITADTPLCNDCALKLFSFLLYK 153

                  ....*
gi 42562591   415 FRITL 419
Cdd:pfam17979 154 YRISI 158

Cysteine rich domain with multizinc binding regions; This is a cysteine rich domain which contains four zinc-binding regions (binding five zinc ions). Family members include human CHFR which interacts with Poly(ADP-ribose) (PAR) through a 20-amino acid PAR binding zinc finger region (PBZ) found at the C-terminal end of this cysteine-rich domain (i.e. the 4th region towards the C-terminal). CHFR lacking PBZ does not co-localize with nuclear PAR foci in interphase cells and cannot rescue antephase checkpoint function despite retaining autoubiquitination activity. Hence it has been suggested that the CHFR-PAR interaction is an important part of the antephase checkpoint and could form part of the checkpoint sensor for cellular stress and microtubule poisons or be required for proper localization of CHFR. The PBZ region of CHFR contains two adenine binding sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591   256 CPQCVANIGGYRCEHHGAHLQCHLCQGMMPFRANLQVPLHCKGCDRPFCGAYWssenvtQGVSGPVCVReTFRPISERTI 335
Cdd:pfam17979   1 CPQCGTAIGGFQCPPQTQHLQCTCCGGMMPDRRDAGVPQQCLLCKRPFCGLYW------GGCPRAGCQG-CLKPFSENLI 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591   336 TRIPFITHEMNRHEQDITQRCIAHMEKTVPDVVAEWLRLFNNREIDRSRMPLNHAET-ITASTHVCNDCYDKLVGFLLYW 414
Cdd:pfam17979  74 SKIPDNVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIDRTRKPLNLSDYiITADTPLCNDCALKLFSFLLYK 153

                  ....*
gi 42562591   415 FRITL 419
Cdd:pfam17979 154 YRISI 158

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 42562591   138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRrseekHKHVLCPQC 182
Cdd:pfam00097   1 CPICLEEPKDPVTLLPCGHLFCSKCIRSWLE-----SGNVTCPLC 40

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 42562591 137 KCSICLNIWHDVVtAAPCLHNFCNGC-FSEWMRRSEEKhkhvlCPQCRTTVQ 187
Cdd:COG5574 217 KCFLCLEEPEVPS-CTPCGHLFCLSClLISWTKKKYEF-----CPLCRAKVY 262

Cysteine rich domain with multizinc binding regions; This is a cysteine rich domain which contains four zinc-binding regions (binding five zinc ions). Family members include human CHFR which interacts with Poly(ADP-ribose) (PAR) through a 20-amino acid PAR binding zinc finger region (PBZ) found at the C-terminal end of this cysteine-rich domain (i.e. the 4th region towards the C-terminal). CHFR lacking PBZ does not co-localize with nuclear PAR foci in interphase cells and cannot rescue antephase checkpoint function despite retaining autoubiquitination activity. Hence it has been suggested that the CHFR-PAR interaction is an important part of the antephase checkpoint and could form part of the checkpoint sensor for cellular stress and microtubule poisons or be required for proper localization of CHFR. The PBZ region of CHFR contains two adenine binding sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591   256 CPQCVANIGGYRCEHHGAHLQCHLCQGMMPFRANLQVPLHCKGCDRPFCGAYWssenvtQGVSGPVCVReTFRPISERTI 335
Cdd:pfam17979   1 CPQCGTAIGGFQCPPQTQHLQCTCCGGMMPDRRDAGVPQQCLLCKRPFCGLYW------GGCPRAGCQG-CLKPFSENLI 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591   336 TRIPFITHEMNRHEQDITQRCIAHMEKTVPDVVAEWLRLFNNREIDRSRMPLNHAET-ITASTHVCNDCYDKLVGFLLYW 414
Cdd:pfam17979  74 SKIPDNVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIDRTRKPLNLSDYiITADTPLCNDCALKLFSFLLYK 153

                  ....*
gi 42562591   415 FRITL 419
Cdd:pfam17979 154 YRISI 158

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of 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 B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 42562591 137 KCSICLNIWHDVVTaAPCLHNFCNGCFSE-WMRRSEEKHkhvLCPQCRTTVQY---VGKNHFLKNIQEE 201
Cdd:cd16597   7 TCSICLELFKDPVT-LPCGHNFCGVCIEKtWDSQHGSEY---SCPQCRATFPRrpeLHKNTVLRNIVEQ 71

RING finger, HC subclass, found in really interesting new gene proteins RING1, RING2 and similar proteins; RING1, also known as polycomb complex protein RING1, RING finger protein 1 (RNF1), or RING finger protein 1A (RING1A), is a transcriptional repressor that is associated with the Polycomb group (PcG) protein complex involved in stable repression of gene activity. RING2, also known as huntingtin-interacting protein 2-interacting protein 3, HIP2-interacting protein 3, protein DinG, RING finger protein 1B (RING1B), RING finger protein 2 (RNF2), or RING finger protein BAP-1, is an E3 ubiquitin-protein ligase that interacts with both nucleosomal DNA and an acidic patch on histone H4 to achieve the specific monoubiquitination of K119 on histone H2A (H2AK119ub), thereby playing a central role in histone code and gene regulation. Both RING1 and RING2 are core components of polycomb repressive complex 1 (PRC1) that functions as an E3-ubuiquitin ligase transferring the mono-ubuiquitin mark to the C-terminal tail of Histone H2A at K118/K119. PRC1 is also capable of chromatin compaction, a function not requiring histone tails, and this activity appears important in gene silencing. RING2 acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity. Members of this family contain a C3HC4-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 42562591 138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRRSEEKhkhvlCPQCRTTVQ 187
Cdd:cd16531   4 CPICLGIIKNTMTVKECLHRFCAECIEKALRLGNKE-----CPTCRKHLP 48

RING finger, HC subclass, found in RING finger protein 138 (RNF138) and similar proteins; RNF138, also known as Nemo-like kinase-associated RING finger protein (NARF) or NLK-associated RING finger protein, is an E3 ubiquitin-protein ligase that plays an important role in glioma cell proliferation, apoptosis, and cell cycle. It specifically cooperates with the E2 conjugating enzyme E2-25K (Hip-2/UbcH1), regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF), and further suppresses Wnt-beta-catenin signaling. RNF138, together with three closely related proteins: RNF114, RNF125 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 42562591 138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRRSEEKhkhvlCPQCRTTVQ 187
Cdd:cd16544   5 CPVCQEVLKDPVELPPCRHIFCKACILLALRSSGAR-----CPLCRGPVG 49

RING finger, HC subclass, found in Equid alphaherpesvirus 1 (Equine herpesvirus 1/EHV-1) regulatory protein and similar proteins; EHV-1 regulatory protein belongs to the Vmw110 (IPC0) protein family. It contains a typical C3HC4-type RING-HC finger and binds zinc stably.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 42562591 138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRRSEEkhkhvlCPQCRTTVQYV 189
Cdd:cd23130   3 CPICLDDPEDEAITLPCLHQFCYTCILRWLQTSPT------CPLCKTPVTSI 48

RING finger, HC subclass, found in tripartite motif-containing protein TRIM58 and similar proteins; TRIM58, also known as protein BIA2, is an erythroid E3 ubiquitin-protein ligase induced during late erythropoiesis. It binds and ubiquitinates the intermediate chain of the microtubule motor dynein (DYNC1LI1/DYNC1LI2), stimulating the degradation of the dynein holoprotein complex. It may participate in the erythroblast enucleation process through regulation of nuclear polarization. TRIM58 belongs to the C-IV subclass of 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 B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 42562591 134 EHAKCSICLNIWHDVVTAApCLHNFCNGCFSEWMRRSEEKHKHVL-CPQCR 183
Cdd:cd16606   1 EEARCPVCLDFLQEPVSVD-CGHSFCLRCISEFCEKSDSAQGGVYaCPQCR 50

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 42562591   138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRrseekHKHVLCPQC 182
Cdd:pfam00097   1 CPICLEEPKDPVTLLPCGHLFCSKCIRSWLE-----SGNVTCPLC 40

RING finger, HC subclass, found in tripartite motif-containing proteins, TRIM7, TRIM11 and TRIM27, and similar proteins; TRIM7, TRIM11 and TRIM27, closely related tripartite motif-containing proteins, belong to the C-IV 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, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM7, also known as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90), is an E3 ubiquitin-protein ligase that mediates c-Jun/AP-1 activation by Ras signalling. Its phosphorylation and activation by MSK1 in response to direct activation by the Ras-Raf-MEK-ERK pathway can stimulate TRIM7 E3 ubiquitin ligase activity in mediating Lys63-linked ubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilization. Moreover, TRIM7 binds and activates glycogenin, the self-glucosylating initiator of glycogen biosynthesis. TRIM11, also known as protein BIA1, or RING finger protein 92 (RNF92), is an E3 ubiquitin-protein ligase involved in the development of the central nervous system. It is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 acts as a potential therapeutic target for congenital central hypoventilation syndrome (CCHS) by mediating the degradation of CCHS-associated polyalanine-expanded Phox2b. TRIM11 modulates the function of neurogenic transcription factor Pax6 through the ubiquitin-proteosome system, and thus plays an essential role for Pax6-dependent neurogenesis. It also binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105), humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults, and further regulates ARC105 function in transforming growth factor beta (TGFbeta) signaling. Moreover, TRIM11 negatively regulates retinoic acid-inducible gene-I (RIG-I)-mediated interferon-beta (IFNbeta) production and antiviral activity by targeting TANK-binding kinase-1 (TBK1). It may contribute to the endogenous restriction of retroviruses in cells. It enhances N-tropic murine leukemia virus (N-MLV) entry by interfering with Ref1 restriction. It also suppresses the early steps of human immunodeficiency virus HIV-1 transduction, resulting in decreased reverse transcripts. TRIM27, also known as RING finger protein 76 (RNF76), RET finger protein (RFP), or zinc finger protein RFP, is a nuclear E3 ubiquitin-protein ligase that is highly expressed in testis and in various tumor cell lines. Expression of TRIM27 is associated with prognosis of colon and endometrial cancers. TRIM27 was first identified as a fusion partner of the RET receptor tyrosine kinase. It functions as a transcriptional repressor and associates with several proteins involved in transcriptional activity, such as enhancer of polycomb 1 (Epc1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex, and the cell cycle regulator retinoblastoma protein (RB1). It also interacts with HDAC1, leading to downregulation of thioredoxin binding protein 2 (TBP-2), which inhibits the function of thioredoxin. Moreover, TRIM27 mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy. In addition, it inhibits muscle differentiation by modulating serum response factor (SRF) and Epc1. TRIM27 promotes a non-canonical polyubiquitination of PTEN, a lipid phosphatase that catalyzes PtdIns(3,4,5)P3 (PIP3) to PtdIns(4,5)P2 (PIP2). It is an IKKepsilon-interacting protein that regulates IkappaB kinase (IKK) function and negatively regulates signaling involved in the antiviral response and inflammation. TRIM27 also forms a protein complex with MBD4 or MBD2 or MBD3, and thus plays an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis. It is a component of an estrogen receptor 1 (ESR1) regulatory complex that is involved in estrogen receptor-mediated transcription in MCF-7 cells.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 42562591 134 EHAKCSICLNIWHDVVTaAPCLHNFCNGCFSEWMRRSEEKHkhvLCPQCRTTVQ 187
Cdd:cd16594   4 EELTCPICLDYFTDPVT-LDCGHSFCRACIARCWEEPETSA---SCPQCRETCP 53

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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591 138 CSICLNIWHDVVTAApCLHNFCNGCFSEWMRRSEEkhkhvlCPQCRTTVQYVGKNHFLKN 197
Cdd:cd16535   4 CSICSELFIEAVTLN-CSHSFCSYCITEWMKRKKE------CPICRKPITSKTRSLVLDN 56

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).

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 42562591 137 KCSICL-NIWHDVVTAAPCLHNFCNGCFSEWMRRSEEkhkhvlCPQCRT 184
Cdd:cd16574   3 SCPICLdRFENEKAFLDGCFHAFCFTCILEWSKVKNE------CPLCKQ 45

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 42562591   137 KCSICLNIWHDVVTAAPCLHNFCNGCFSEWMRRSEEkhkhvlCPQC 182
Cdd:pfam13923   1 MCPICMDMLKDPSTTTPCGHVFCQDCILRALEASNE------CPLC 40

RING finger, HC subclass, found in tripartite motif-containing protein 8 (TRIM8) and similar proteins; TRIM8, also known as glioblastoma-expressed RING finger protein (GERP) or RING finger protein 27 (RNF27), is a probable E3 ubiquitin-protein ligase that may promote proteasomal degradation of suppressor of cytokine signaling 1 (SOCS1) and further regulate interferon-gamma signaling. It functions as a new p53 modulator that stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation. TRIM8 deficit dramatically impairs p53 stabilization and activation in response to chemotherapeutic drugs. TRIM8 also modulates tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta)-triggered nuclear factor-kappaB (NF- kappa B) activation by targeting transforming growth factor beta (TGFbeta) activated kinase 1 (TAK1) for K63-linked polyubiquitination. Moreover, TRIM8 modulates translocation of phosphorylated STAT3 into the nucleus through interaction with Hsp90beta and consequently regulates transcription of Nanog in embryonic stem cells. It also interacts with protein inhibitor of activated STAT3 (PIAS3), which inhibits IL-6-dependent activation of STAT3. TRIM8 belongs to the C-V 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 domain, as well as an uncharacterized region positioned C-terminal to the RBCC domain. The coiled coil domain is required for homodimerization and the region immediately C-terminal to the RING motif is sufficient to mediate the interaction with SOCS1.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 42562591 134 EHAKCSICLNIWHDVVTAaPCLHNFCNGCFSE-WMRRSeekhKHVLCPQC 182
Cdd:cd16580  10 EELICPICLHVFVEPVQL-PCKHNFCRGCIGEaWAKDA----GLVRCPEC 54

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 42562591 137 KCSICLNIWHDVVtAAPCLHNFCNGC-FSEWMRRSEEKhkhvlCPQCRTTVQ 187
Cdd:COG5574 217 KCFLCLEEPEVPS-CTPCGHLFCLSClLISWTKKKYEF-----CPLCRAKVY 262

RING finger, HC subclass, found in peroxin-10 (PEX10) and similar proteins; PEX10, also known as peroxisome biogenesis factor 10, peroxisomal biogenesis factor 10, peroxisome assembly protein 10, or RING finger protein 69 (RNF69), is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C-terminus. It plays an essential role in peroxisome assembly, import of target substrates, and recycling or degradation of protein complexes and amino acids. It is an essential component of the spinal locomotor circuit, and thus its mutations may be involved in peroxisomal biogenesis disorders (PBD). Mutations in human PEX10 also result in autosomal recessive ataxia. Moreover, PEX10 functions as an E3-ubiquitin ligase with an E2, UBCH5C. It mono- or poly-ubiquitinates PEX5, a key player in peroxisomal matrix protein import, in a UBC4-dependent manner, to control PEX5 receptor recycling or degradation. It also links the E2 ubiquitin conjugating enzyme PEX4 to the protein import machinery of the peroxisome.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 42562591 136 AKCSICLNIWHDVvTAAPCLHNFCNGCFSEWMRRSEEkhkhvlCPQCRTTVQ 187
Cdd:cd16527   1 RKCSLCLEERRHP-TATPCGHLFCWSCITEWCNEKPE------CPLCREPFQ 45

RING finger found in polycomb group RING finger protein 2 (PCGF2) and similar proteins; PCGF2, also known as DNA-binding protein Mel-18, RING finger protein 110 (RNF110), or zinc finger protein 144 (ZNF144), is one of six PcG RING finger (PCGF) homologs (PCGF1/NSPc1, PCGF2/Mel-18, PCGF3, PCGF4/BMI1, PCGF5, and PCGF6/MBLR). It serves as the core component of a canonical Polycomb repressive complex 1 (PRC1), which is composed of a chromodomain-containing protein (CBX2, CBX4, CBX6, CBX7 or CBX8) and a Polyhomeotic protein (PHC1, PHC2, or PHC3). Like other PCGF homologs, PCGF2 associates with ring finger protein 2 (RNF2) to form a RNF2-PCGF heterodimer, which is catalytically competent as an E3 ubiquitin transferase and is the scaffold for the assembly of additional components. Moreover, PCGF2 uniquely regulates PRC1 to specify mesoderm cell fate in embryonic stem cells. It is required for PRC1 stability and maintenance of gene repression in embryonic stem cells (ESCs) and essential for ESC differentiation into early cardiac-mesoderm precursors. PCGF2 also plays a significant role in the angiogenic function of endothelial cells (ECs) by regulating endothelial gene expression. Furthermore, PCGF2 is a SUMO-dependent regulator of hormone receptors. It facilitates the deSUMOylation process by inhibiting PCGF4/BMI1-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). It is also a novel negative regulator of breast cancer stem cells (CSCs) that inhibits the stem cell population and in vitro and in vivo self-renewal through the inactivation of Wnt-mediated Notch signaling. PCGF2 contains a C3HC4-type RING-HC finger.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 42562591 123 RTQLLQISIDPEHAKCSICLNIWHDVVTAAPCLHNFCNGCFSEWMrrseEKHKHvlCPQCRTTVQ 187
Cdd:cd16734   2 RTTRIKITELNPHLMCALCGGYFIDAATIVECLHSFCKTCIVRYL----ETNKY--CPMCDVQVH 60

RING finger found in polycomb group RING finger protein 5 (PCGF5) and similar proteins; PCGF5, also known as RING finger protein 159 (RNF159), is one of six PcG RING finger (PCGF) homologs (PCGF1/NSPc1, PCGF2/Mel-18, PCGF3, PCGF4/BMI1, PCGF5, and PCGF6/MBLR) and serves as the core component of a Polycomb repressive complex 1 (PRC1). Like other PCGF homologs, PCGF5 associates with ring finger protein 2 (RNF2) to form a RNF2-PCGF heterodimer, which is catalytically competent as an E3 ubiquitin transferase and is the scaffold for the assembly of additional components. PCGF5 contains a C3HC4-type RING-HC finger.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 42562591 138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRRSeekhkhVLCPQCrttvqyvgKNHFLKNIQEEILKVDAALR 210
Cdd:cd16737  13 CRICKGYLIKPTTVTECLHTFCKSCIVQHFEDS------NDCPEC--------GIQVHETNPLEMLRLDNTLE 71

Variant RING finger, HC subclass (C4C4-type), found in retinoblastoma-binding protein 6 (RBBP6) and similar proteins; RBBP6, also known as proliferation potential-related protein, protein P2P-R, retinoblastoma-binding Q protein 1 (RBQ-1), or p53-associated cellular protein of testis (PACT), is a nuclear E3 ubiquitin-protein ligase involved in multiple processes, such as the control of gene expression, mitosis, cell differentiation, and cell apoptosis. It plays a role in both promoting and inhibiting apoptosis in many human cancers, including esophageal, lung, hepatocellular, and colon cancers, familial myeloproliferative neoplasms, as well as in human immunodeficiency virus-associated nephropathy (HIVAN). It functions as an Rb- and p53-binding protein that plays an important role in chaperone-mediated ubiquitination and possibly in protein quality control. It acts as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in an increase of MDM2-mediated ubiquitination and degradation of p53/TP53, and leading to both apoptosis and cell growth. It is also a double-stranded RNA-binding protein that plays a role in mRNA processing by regulating the human polyadenylation machinery and modulating expression of mRNAs with AU-rich 3' untranslated regions (UTRs). Moreover, RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38 that negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Furthermore, RBBP6 is involved in tunicamycin-induced apoptosis by mediating protein kinase (PKR) activation. RBBP6 contains an N-terminal ubiquitin-like domain and a C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger. RBBP6 interacts with chaperones Hsp70 and Hsp40 through its N-terminal ubiquitin-like domain. It promotes the ubiquitination of p53 by Hdm2 in an E4-like manner through its RING finger. It also interacts directly with the pro-proliferative transcription factor Y-box-binding protein-1 (YB-1) via its RING finger.

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                ....*....|....*....|....*....|....*....|....*....|....*
gi 42562591 133 PEHAKCSICLNIWHDVVTAAPCLHNFCNGCfsewmRRSEEKHKHVLCPQCRTTVQ 187
Cdd:cd16620   1 PDELKCPICKDLMKDAVLTPCCGNSFCDEC-----IRTALLEEDFTCPTCKEPDV 50

RING-finger-containing ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

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                ....*....|....*....|....*....|....*....|....*....|.
gi 42562591 138 CSICLN--IWHDVVTAAPCLHNFCNGCFSEWMRrseeKHKHVlCPQCRTTV 186
Cdd:COG5540 326 CAICMSnfIKNDRLRVLPCDHRFHVGCVDKWLL----GYSNK-CPVCRTAI 371

RING finger, HC subclass, found in tripartite motif-containing protein 45 (TRIM45) and similar proteins; TRIM45, also known as RING finger protein 99 (RNF99), is a novel receptor for activated C-kinase (RACK1)-interacting protein that suppresses transcriptional activities of Elk-1 and AP-1 and downregulates mitogen-activated protein kinase (MAPK) signal transduction through inhibiting RACK1/PKC (protein kinase C) complex formation. It also negatively regulates tumor necrosis factor alpha (TNFalpha)-induced nuclear factor-kappaB (NF-kappa B)-mediated transcription and suppresses cell proliferation. TRIM45 belongs to the C-VII subclass of the TRIM (tripartite motif) family that is 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 filamin-type immunoglobulin (IG-FLMN) domain and NHL repeats positioned C-terminal to the RBCC domain.

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                ....*....|....*....|....*....|....*....|
gi 42562591 153 PCLHNFCNGCFSEWM----------RRSEEKHKHVLCPQC 182
Cdd:cd16588  17 PCLHTLCSPCLRQLEpfsvcglrggDRSEKSNYSVLCPVC 56

RING finger, HC subclass, found in helicase-like transcription factor (HLTF) and similar proteins; HLTF, also known as DNA-binding protein/plasminogen activator inhibitor 1 regulator, HIP116, RING finger protein 80, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 3, or sucrose nonfermenting protein 2-like 3, is a yeast RAD5 homolog found in mammals. It has both E3 ubiquitin ligase and DNA helicase activities, and plays a pivotal role in the template-switching pathway of DNA damage tolerance. It is involved in Lys-63-linked poly-ubiquitination of proliferating cell nuclear antigen (PCNA) at Lys-164 and in the regulation of DNA damage tolerance. It shows double-stranded DNA translocase activity with 3'-5' polarity, thereby facilitating regression of the replication fork. HLTF contains an N-terminal HIRAN (HIP116 and RAD5 N-terminal) domain, a SWI/SNF helicase domain that is divided into N- and C-terminal parts by an insertion of a C3HC4-type RING-HC finger involved in the poly-ubiquitination of PCNA.

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                ....*....|....*....|....*....|....*....|....*....|.
gi 42562591 138 CSICLNIWHD-VVTaaPCLHNFCNGCFSEWMRRSEEKhkhvlCPQCRTTVQ 187
Cdd:cd16509   6 CAICLDSLTNpVIT--PCAHVFCRRCICEVIQREKAK-----CPMCRAPLS 49

RING finger, HC subclass, found in tripartite motif-containing protein 77 (TRIM77) and similar proteins; TRIM77 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including two consecutive zinc-binding domains, a C3HC4-type RING-HC finger and Bbox2, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain.

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                ....*....|....*....|....*....|....*....|....*....|.
gi 42562591 138 CSICLNIWHDVVTAaPCLHNFCNGCFSE-WMRRSEEKHkhvlCPQCRTTVQ 187
Cdd:cd16543   6 CSICLDLLKDPVTI-PCGHSFCMNCITLlWDRKQGVPS----CPQCRESFP 51

RING finger, HC subclass, found in RING finger protein 168 (RNF168) and similar proteins; RNF168 is an E3 ubiquitin-protein ligase that promotes noncanonical K27 ubiquitination to signal DNA damage. It, together with RNF8, functions as a DNA damage response (DDR) factor that promotes a series of ubiquitylation events on substrates, such as H2A and H2AX with H2AK13/15 ubiquitylation, facilitates recruitment of repair factors p53-binding protein 1 (53BP1) or the RAP80-BRCA1 complex to sites of double-strand breaks (DSBs), and inhibits homologous recombination (HR) in cells deficient in the tumor suppressor BRCA1. RNF168 also promotes H2A neddylation, which antagonizes ubiquitylation of H2A and regulates DNA damage repair. Moreover, RNF168 forms a functional complex with RAD6A or RAD6B during the DNA damage response. RNF168 contains an N-terminal C3HC4-type RING-HC finger that catalyzes H2A-K15ub and interacts with H2A, and two MIU (motif interacting with ubiquitin) domains responsible for the interaction with K63 linked poly-ubiquitin.

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                ....*....|....*....|....*....|....*....|....*....
gi 42562591 138 CSICLNIWHDVVTAaPCLHNFCNGCFSEWMRRSeekhkHVLCPQCRTTV 186
Cdd:cd16550   3 CPICLEILVEPVTL-PCNHTLCMPCFQSTVEKA-----SLCCPLCRLRI 45

RING finger, HC subclass, found in Schizosaccharomyces pombe DNA repair protein Rad8 (SpRad8) and similar proteins; SpRad8 is a conserved protein homologous to Saccharomyces cerevisiae DNA repair protein Rad5 and human helicase-like transcription factor (HLTF) that is required for error-free postreplication repair by contributing to polyubiquitylation of PCNA. SpRad8 contains a C3HC4-type RING-HC finger responsible for the E3 ubiquitin ligase activity, a SNF2-family helicase domain including an ATP binding site, and a family-specific HIRAN domain (HIP116, Rad5p N-terminal domain) that contributes to nuclear localization.

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                ....*....|....*....|....*....|....*....|....*....
gi 42562591 138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRRSEEKHKHVLCPQCRTTV 186
Cdd:cd16572   7 CPICAEEPISELALTRCWHSACKDCLLDHIEFQKSKNEVPLCPTCRQPI 55

RING finger, HC subclass, found in RING finger protein 220 (RNF220) and similar proteins; RNF220 is an E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of Sin3B, a scaffold protein of the Sin3/HDAC (histone deacetylase) corepressor complex. It can also bind E2 and mediate auto-ubiquitination of itself. Moreover, RNF220 specifically interacts with beta-catenin, and enhances canonical Wnt signaling through ubiquitin-specific protease 7 (USP7)-mediated deubiquitination and stabilization of beta-catenin, which is independent of its E3 ligase activity. RNF220 contains a characteristic C3HC4-type RING-HC finger at its C-terminus.

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                ....*....|....*....|....*....|....*....|....*.
gi 42562591 137 KCSICLNIWHDVVTAAPCLHNFCNGCfseWMRRSEEKHkhvLCPQC 182
Cdd:cd16563   2 KCLICMDSYTMPLVSIQCWHVHCEEC---WLRTLGAKK---LCPQC 41

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM13, TRIM59 and similar proteins; TRIM13 and TRIM59, two closely related tripartite motif-containing proteins, belong to the C-V subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domain, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, followed by a C-terminal transmembrane domain. TRIM13, also known as B-cell chronic lymphocytic leukemia tumor suppressor Leu5, leukemia-associated protein 5, putative tumor suppressor RFP2, RING finger protein 77 (RNF77), or Ret finger protein 2, is an endoplasmic reticulum (ER) membrane anchored E3 ubiquitin-protein ligase that interacts with proteins localized to the ER, including valosin-containing protein (VCP), a protein indispensable for ER-associated degradation (ERAD). TRIM59, also known as RING finger protein 104 (RNF104) or tumor suppressor TSBF-1, is a putative E3 ubiquitin-protein ligase that functions as a novel multiple cancer biomarker for immunohistochemical detection of early tumorigenesis.

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                ....*....|....*....|....*....|....*....|....*..
gi 42562591 138 CSICLNIWHDVvTAAPCLHNFCNGCFSEWMRRSEEKHKHVL-CPQCR 183
Cdd:cd16581   5 CSICYNIFDDP-KILPCSHTFCKNCLEKLLAASGYYLLASLkCPTCR 50

RING finger, HC subclass, found in Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) and similar proteins; AtRMAs, including AtRma1, AtRma2, and AtRma3, are endoplasmic reticulum (ER)-localized Arabidopsis homologs of human outer membrane of the ER-anchor E3 ubiquitin-protein ligase, RING finger protein 5 (RNF5). AtRMAs possess E3 ubiquitin ligase activity, and may play a role in the growth and development of Arabidopsis. The AtRMA1 and AtRMA3 genes are predominantly expressed in major tissues, such as cotyledons, leaves, shoot-root junction, roots, and anthers, while AtRMA2 expression is restricted to the root tips and leaf hydathodes. AtRma1 probably functions with the Ubc4/5 subfamily of E2. AtRma2 is likely involved in the cellular regulation of ABP1 expression levels through interacting with auxin binding protein 1 (ABP1). AtRMA proteins contain an N-terminal C3HC4-type RING-HC finger and a trans-membrane-anchoring domain in their extreme C-terminal region.

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                ....*....|....*....|....*....|....*....|....*..
gi 42562591 138 CSICLNIWHD-VVTAapCLHNFCNGCFSEWMRRSEEKHKhvlCPQCR 183
Cdd:cd16745   3 CNICLDLAQDpVVTL--CGHLFCWPCLHKWLRRQSSQPE---CPVCK 44

RING finger, HC subclass, found in SH3 domain-containing RING finger protein 2 (SH3RF2) and similar proteins; SH3RF2, also known as heart protein phosphatase 1-binding protein (HEPP1), plenty of SH3s (POSH)-eliminating RING protein (POSHER), protein phosphatase 1 regulatory subunit 39, or RING finger protein 158 (RNF158), is a putative E3 ubiquitin-protein ligase that acts as an anti-apoptotic regulator for the c-Jun N-terminal kinase (JNK) pathway by binding to and promoting the proteasomal degradation of SH3RF1 (or POSH), a scaffold protein that is required for pro-apoptotic JNK activation. It may also play a role in cardiac functions together with protein phosphatase 1. SH3RF2 contains an N-terminal C3HC4-type RING-HC finger responsible for the E3 ligase activity and four Src Homology 3 (SH3) domains, which are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs.

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                ....*....|....*....|....*....|....*....|....*...
gi 42562591 137 KCSICLNIWHDVVTAAPCLHNFCNGCfsewMRRSEEKHKHVLCPQCRT 184
Cdd:cd16749   2 ECPVCFEKLDVTAKVLPCQHTFCKPC----LQRIFKARKELRCPECRT 45

RING finger, HC subclass, found in breast cancer type 1 susceptibility protein (BRCA1) and similar proteins; BRCA1, also known as RING finger protein 53 (RNF53), is a RING finger protein encoded by the tumor suppressor gene BRCA1 that regulates all DNA double-strand break (DSB) repair pathways. BRCA1 is frequently mutated in patients with hereditary breast and ovarian cancer (HBOC). Its mutation is also associated with an increased risk of pancreatic, stomach, laryngeal, fallopian tube, and prostate cancer. It plays an important role in the DNA damage response signaling and has been implicated in various cellular processes such as cell cycle regulation, transcriptional regulation, chromatin remodeling, DNA DSBs, and apoptosis. BRCA1 contains an N-terminal C3HC4-type RING-HC finger, and two BRCT (BRCA1 C-terminus domain) repeats at the C-terminus.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 42562591 138 CSICLNIWHDVVTAApCLHNFCNGCFSEWMrrsEEKHKHVLCPQCRT--TVQYVGKNHFLKNIQEEILKV 205
Cdd:cd16498  19 CPICLELLKEPVSTK-CDHQFCRFCILKLL---QKKKKPAPCPLCKKsvTKRSLQESTRFKQLVEAVKKL 84

RING finger, HC subclass, found in RING finger protein 166 (RNF166) and similar proteins; RNF166 is encoded by the gene RNF166 targeted by thyroid hormone receptor alpha1 (TRalpha1), which is important in brain development. It plays an important role in RNA virus-induced interferon-beta production by enhancing the ubiquitination of TRAF3 and TRAF6. RNF166, together with three closely related proteins: RNF114, RNF125 and RNF138, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

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                ....*....|....*....|....*....|....*....|....*.
gi 42562591 138 CSICLNIWHDVVTAAPCLHNFCNGCFSEWMRRSEEkhkhvLCPQCR 183
Cdd:cd16549   4 CPICLEVYHKPVVITSCGHTFCGECLQPCLQVASP-----LCPLCR 44