forkhead associated (FHA) domain found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also called RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22 and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated-(FHA) domain and a RING-HC finger. The CHFR FHA domain has been crystallized as a segment-swapped dimer. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  15 PWGRLLRLGaEEDEPQILLWKREWTIGRRRGCDLSFPSNKLVSGDHCKLRVDEKsGEVTLEDTSTNGTVINKLRVVKKQT 94
Cdd:cd22672    1 AWGQLVRLT-EESSPPILLRKDEFTIGRAKDCDLSFPGNKLVSGDHCKIIRDEK-GQVWLEDTSTNGTLVNKVKVVKGQK 78

                         90       100       110
                 ....*....|....*....|....*....|
gi 564379885  95 YPLQSGDIIYLVYRKNEPEHNVAYLYESLN 124
Cdd:cd22672   79 VELKHGDVIYLVYRKNDPEQNVAYLFQSLS 108

RING finger, HC subclass, found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also known as RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22, and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression, and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated (FHA) domain and a C3HC4-type RING-HC finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 564379885 299 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSS-LCPTCRCPVERICKNH 352
Cdd:cd16503    1 ENLTCSICQDLLHDCVSLQPCMHNFCAACYSDWMERSNtECPTCRATVQRVNKNH 55

PBZ domain; This domain is a zinc-finger motif that in humans is part of the APLF, aprataxin- and PNK-like forkhead association domain-containing protein. The ZnF is highly conserved both in primary sequence and in the spacing between the putative zinc coordinating residues and is configured CX5CX6HX5H. Many of the proteins containing the APLF-like ZnF are involved in DNA strand break repair and/or contain domains implicated in DNA metabolism.

                          10        20
                  ....*....|....*....|....
gi 564379885  592 RPDCYWGRNCRTQvKAHHAMKFNH 615
Cdd:pfam10283   1 RPPCKYGAKCYRK-NPQHFKEFSH 23

forkhead associated (FHA) domain found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also called RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22 and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated-(FHA) domain and a RING-HC finger. The CHFR FHA domain has been crystallized as a segment-swapped dimer. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  15 PWGRLLRLGaEEDEPQILLWKREWTIGRRRGCDLSFPSNKLVSGDHCKLRVDEKsGEVTLEDTSTNGTVINKLRVVKKQT 94
Cdd:cd22672    1 AWGQLVRLT-EESSPPILLRKDEFTIGRAKDCDLSFPGNKLVSGDHCKIIRDEK-GQVWLEDTSTNGTLVNKVKVVKGQK 78

                         90       100       110
                 ....*....|....*....|....*....|
gi 564379885  95 YPLQSGDIIYLVYRKNEPEHNVAYLYESLN 124
Cdd:cd22672   79 VELKHGDVIYLVYRKNDPEQNVAYLFQSLS 108

RING finger, HC subclass, found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also known as RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22, and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression, and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated (FHA) domain and a C3HC4-type RING-HC finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 564379885 299 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSS-LCPTCRCPVERICKNH 352
Cdd:cd16503    1 ENLTCSICQDLLHDCVSLQPCMHNFCAACYSDWMERSNtECPTCRATVQRVNKNH 55

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 564379885   38 WTIGRRRGCDLSFPSnKLVSGDHCKLRVDEkSGEVTLEDT-STNGTVINKLRvVKKQTYPLQSGDIIYL 105
Cdd:pfam00498   1 VTIGRSPDCDIVLDD-PSVSRRHAEIRYDG-GGRFYLEDLgSTNGTFVNGQR-LGPEPVRLKDGDVIRL 66

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 564379885  302 TCIICQDLL--HDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:pfam13639   2 ECPICLEEFeeGDKVVVLPCGHHFHRECLDKWLRSSNTCPLCR 44

type VI secretion system FHA domain protein; Members of this protein family are FHA (forkhead-associated) domain-containing proteins that are part of type VI secretion loci in a considerable number of bacteria, most of which are known pathogens. Species include Pseudomonas aeruginosa PAO1, Aeromonas hydrophila, Yersinia pestis, Burkholderia mallei, etc. [Protein fate, Protein and peptide secretion and trafficking, Cellular processes, Pathogenesis]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885   26 EDEPQILLWKREWTIGRRRGCDLSFPS-NKLVSGDHCKLRVDEksGEVTLEDTSTNGTVINKL--RVVKKQTYPLQSGDI 102
Cdd:TIGR03354  14 GIAAQKTFGTNGGTIGRSEDCDWVLPDpERHVSGRHARIRYRD--GAYLLTDLSTNGVFLNGSgsPLGRGNPVRLEQGDR 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  103 IYL-------------VYRKNEPEHNVAYLYEslNGKQSLTQESLEANKENMFHVTKESSGPGQGDDPQVPLLSPMAQTc 169
Cdd:TIGR03354  92 LRLgdyeirvslgdplVSRQASESRADTSLPT--AGGPPTPDPAPLAQLDPLKALDQEPLSAADLDDLSAPLFPPLDAR- 168

                         170       180
                  ....*....|....*....|....*.
gi 564379885  170 leepQPststSDLLPTASTSSTEPEL 195
Cdd:TIGR03354 169 ----LP----AFAAPIDAEPTMVPPF 186

HRD ubiquitin ligase complex, ER membrane component [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 564379885 302 TCIICQDLLHDCVSLQ------------PCMHTFCAACYSGWMERSSLCPTCRCPV 345
Cdd:COG5243  289 TCTICMDEMFHPDHEPlprgldmtpkrlPCGHILHLHCLKNWLERQQTCPICRRPV 344

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 564379885    38 WTIGRRR-GCDLSFPSNKlVSGDHCKLRVDEKsGEVTLEDT-STNGTVINKLRV 89
Cdd:smart00240   1 VTIGRSSeDCDIQLDGPS-ISRRHAVIVYDGG-GRFYLIDLgSTNGTFVNGKRI 52

forkhead associated (FHA) domain found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also called RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22 and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated-(FHA) domain and a RING-HC finger. The CHFR FHA domain has been crystallized as a segment-swapped dimer. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  15 PWGRLLRLGaEEDEPQILLWKREWTIGRRRGCDLSFPSNKLVSGDHCKLRVDEKsGEVTLEDTSTNGTVINKLRVVKKQT 94
Cdd:cd22672    1 AWGQLVRLT-EESSPPILLRKDEFTIGRAKDCDLSFPGNKLVSGDHCKIIRDEK-GQVWLEDTSTNGTLVNKVKVVKGQK 78

                         90       100       110
                 ....*....|....*....|....*....|
gi 564379885  95 YPLQSGDIIYLVYRKNEPEHNVAYLYESLN 124
Cdd:cd22672   79 VELKHGDVIYLVYRKNDPEQNVAYLFQSLS 108

RING finger, HC subclass, found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also known as RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22, and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression, and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated (FHA) domain and a C3HC4-type RING-HC finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 564379885 299 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSS-LCPTCRCPVERICKNH 352
Cdd:cd16503    1 ENLTCSICQDLLHDCVSLQPCMHNFCAACYSDWMERSNtECPTCRATVQRVNKNH 55

forkhead associated (FHA) domain superfamily; Forkhead-associated (FHA) domains are small phosphopeptide recognition modules mostly found in eubacteria and eukaryotes. It is about 95-120 residues long that fold into an 11-stranded beta-sandwich. FHA domains can mediate the recognition of phosphorylated and non-phosphorylated substrates, as well as protein oligomerization. They specifically recognize threonine phosphorylation (pThr) accompanying activation of protein serine/threonine kinases. FHA domains show diverse ligand specificity. They may recognize the pTXXD motif, the pTXXI/L motif, and TQ clusters (singly and multiply phosphorylated). In eukaryotes, FHA superfamily members include forkhead-type transcription factors, as well as other signaling proteins, such as many regulatory proteins, kinases, phosphatases, motor proteins called kinesins, and metabolic enzymes. Many of them localize to the nucleus, where they participate in establishing or maintaining cell cycle checkpoints, DNA repair, or transcriptional regulation. FHA domains play important roles in human diseases, particularly in relation to DNA damage responses and cancers. In bacteria, FHA domain-containing proteins may participate in injection of viral proteins into host cells, transmembrane transporters, and cell division. FHA domain-containing proteins rarely include more than one copy of the domain. The only exception in eukaryotes is the checkpoint kinase Rad53 from Saccharomyces cerevisiae, which harbors two FHA domains (FHA1 and FHA2) flanking a central kinase domain. The two FHA domains recognize different phosphorylated targets and function independently from one another. In contrast, Mycobacterium tuberculosis ABC transporter Rv1747 contains two FHA domains but only one of them is essential for protein function.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  18 RLLRLGAEEDEPQILLWKREWTIGRRRGCDLSFPsNKLVSGDHCKLRVDEksGEVTLEDT-STNGTVINKLRVVKKqtYP 96
Cdd:cd00060    1 RLIVLDGDGGGREFPLTKGVVTIGRSPDCDIVLD-DPSVSRRHARIEVDG--GGVYLEDLgSTNGTFVNGKRITPP--VP 75

                 ....*....
gi 564379885  97 LQSGDIIYL 105
Cdd:cd00060   76 LQDGDVIRL 84

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 564379885   38 WTIGRRRGCDLSFPSnKLVSGDHCKLRVDEkSGEVTLEDT-STNGTVINKLRvVKKQTYPLQSGDIIYL 105
Cdd:pfam00498   1 VTIGRSPDCDIVLDD-PSVSRRHAEIRYDG-GGRFYLEDLgSTNGTFVNGQR-LGPEPVRLKDGDVIRL 66

Predicted component of the type VI protein secretion system, contains a FHA domain [Signal transduction mechanisms, Intracellular trafficking, secretion, and vesicular transport];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  39 TIGRRRGCDLSFP-SNKLVSGDHCKLRVDEksGEVTLEDTSTNGTVIN--KLRVVKKQTYPLQSGDII----Y--LVYRK 109
Cdd:COG3456   29 TIGRSADCDWVLPdPDRSVSRRHAEIRFRD--GAFCLTDLSTNGTFLNgsDHPLGPGRPVRLRDGDRLrigdYeiRVEIS 106

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885 110 NEPEHNVAYLYEslngkQSLTQESLEANKENMFHVTKESSGPGQGDDPQVPLLSPMAqtclEEPQPSTSTSDLLPTASTS 189
Cdd:COG3456  107 GEDEGADDPLAA-----APEPAVSSPSNLSDTEAAPDAALAFSFSLDPLEALDEAAT----EAPATADDPPSLLPEDWLP 177

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 564379885 190 STEPeltSAGQKHSSSSGPGTISISPKECSSLVANGELSSLSSVFQDNEASFSLLKTEDTEEL 252
Cdd:COG3456  178 SAAP---VADEAAAQAIDQLPSAAAPAPEPEPAADADHALLAALLRGLGLDLELLDSQDAEDF 237

forkhead associated (FHA) domain found in Bdellovibrio bacteriovorus GGDEF domain protein DgcB and similar proteins; DgcB is a GGDEF enzyme that produces cyclic-di-GMP in response to an unknown stimulus. It appends the C-terminal GGDEF enzymatic domain with an N-terminal forkhead-associated (FHA) domain that acts as a consensus phosphopeptide sensor. The GGDEF and sensory FHA domains form an asymmetrical dimer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  19 LLRLGAEEDEPQILLWKREWTIGRRRGCDLSFPsNKLVSGDHCKLRVDekSGEVTLEDT-STNGTVINKLRVVKKQTYPL 97
Cdd:cd22682    3 LMIIGPPGVGKQFPITESTIVIGRSVESQVQID-DDSVSRYHAKLAVN--PSAVSIIDLgSTNGTIVNGKKIPKLASCDL 79

                 ....*.
gi 564379885  98 QSGDII 103
Cdd:cd22682   80 QNGDQI 85

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885 297 MEETLTCIICQDLLHDCVSLqPCMHTFCAACYSG-WME---RSSLCPTCRCPVER---ICKNHILNNLVE 359
Cdd:cd16597    2 LEEELTCSICLELFKDPVTL-PCGHNFCGVCIEKtWDSqhgSEYSCPQCRATFPRrpeLHKNTVLRNIVE 70

forkhead associated (FHA) domain found in transcription factor 19 (TCF-19) and similar proteins; TCF-19, also called transcription factor SC1, was identified as a putative trans-activating factor with expression beginning at the late G1-S boundary in dividing cells. It also functions as a novel islet factor necessary for proliferation and survival in the INS-1 beta cell line. It plays an important role in susceptibility to both Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM); it has been suggested that it may positively impact beta cell mass under conditions of beta cell stress and increased insulin demand. TCF-19 contains an N-terminal fork head association domain (FHA), a proline rich region, and a C-terminal plant homeodomain (PHD) finger. The FHA domain may serve as a nuclear signaling domain or as a phosphoprotein binding domain. The proline rich region is a common characteristic of trans-activating factors. The PHD finger may allow TCF-19 to interact with chromatin via methylated histone H3.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  18 RLLRLG------AEEDEPQILLWKREWTIGRRRG-CDLSFPSN---KLVSGDHCKLRV---DEKSGEVTLEDTSTNGTVI 84
Cdd:cd22685    4 QLLRIGlsasrsEPRDLYTFRPDLCEYRIGRNPEvCDVFLCSSqhpNLISREHAEIHAerdGNGNWKVLIEDRSTNGTYV 83

                         90
                 ....*....|....*....
gi 564379885  85 NKLRVVKKQTYPLQSGDII 103
Cdd:cd22685   84 NDVRLQDGQRRELSDGDTI 102

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  17 GRLLRLGAEEDEPQI-LLWKREWTIGRRRGCDLSFpSNKLVSGDHCKLRVdEKSGEVTLEDTSTNGTVINKLRVVKKqTY 95
Cdd:cd22683    1 GSLVNLIVG*KEQKIsITNRNVTTIGRSRSCDLVL-SDPSISRFHAELRL-EQNGINVIDNNSANGTFINGKRIKGK-TY 77

                         90
                 ....*....|
gi 564379885  96 PLQSGDIIYL 105
Cdd:cd22683   78 ILKNGDIIVF 87

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 564379885  302 TCIICQDLL--HDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:pfam13639   2 ECPICLEEFeeGDKVVVLPCGHHFHRECLDKWLRSSNTCPLCR 44

RING finger, HC subclass, found in tripartite motif-containing protein 35 (TRIM35) and similar proteins; TRIM35, also known as hemopoietic lineage switch protein 5 (HLS5), is a putative hepatocellular carcinoma (HCC) suppressor that inhibits phosphorylation of pyruvate kinase isoform M2 (PKM2), which is involved in aerobic glycolysis of cancer cells and further suppresses the Warburg effect and tumorigenicity in HCC. It also negatively regulates Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon production by suppressing the stability of interferon regulatory factor 7 (IRF7). Moreover, TRIM35 regulates erythroid differentiation by modulating globin transcription factor 1 (GATA-1) activity. TRIM35 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 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 564379885 298 EETLTCIICQDLLHDCVSLqPCMHTFCAACYSGWMER--SSLCPTCR--CPVERICKNHILNNLVE 359
Cdd:cd16599    2 KEELLCPICYEPFREAVTL-RCGHNFCKGCVSRSWERqpRAPCPVCKeaSSSDDLRTNHTLNNLVE 66

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
                 ....*....|....*....|....*....|....*....|....*...
gi 564379885 299 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSL-CPTCRCPV 345
Cdd:cd16544    1 AELTCPVCQEVLKDPVELPPCRHIFCKACILLALRSSGArCPLCRGPV 48

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564379885  18 RLLRLGAEEDEPQILLW-KREWTIGRRRG--CDLSFPSNKLVSGDHCKLRVDEkSGEVTLED-TSTNGTVINKLRVVKKQ 93
Cdd:cd22663    2 CLRRVGHGIDPLVLLLEdGKEVTVGRGLGvtYQLVSTCPLMISRNHCVLKKND-EGQWTIKDnKSLNGVWVNGERIEPLK 80

                         90
                 ....*....|..
gi 564379885  94 TYPLQSGDIIYL 105
Cdd:cd22663   81 PYPLNEGDLIQL 92

RING finger, H2 subclass, found in synoviolin and similar proteins; Synoviolin, also known as synovial apoptosis inhibitor 1 (Syvn1), Hrd1, or Der3, is an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis and plays a role in homeostasis maintenance. It also targets tumor suppressor gene p53 for proteasomal degradation, suggesting crosstalk between ER associated degradation (ERAD) and p53 mediated apoptotic pathway under ER stress. Moreover, synoviolin controls body weight and mitochondrial biogenesis through negative regulation of the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1beta. It upregulates amyloid beta production by targeting a negative regulator of gamma-secretase, Retention in endoplasmic reticulum 1 (Rer1), for degradation. It is also involved in the degradation of endogenous immature nicastrin, and affects amyloid beta-protein generation. Moreover, synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of rheumatoid arthritis (RA). It functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of RA. It promotes inositol-requiring enzyme 1 (IRE1) ubiquitination and degradation in synovial fibroblasts with collagen-induced arthritis. Furthermore, the upregulation of synoviolin may represent a protective response against neurodegeneration in Parkinson's disease (PD). In addition, synoviolin is involved in liver fibrogenesis. Synoviolin contains a C3H2C2-type RING-H2 finger.

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gi 564379885 302 TCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:cd16479    3 TCIICREEMTVGAKKLPCGHIFHLSCLRSWLQRQQTCPTCR 43

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.

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gi 564379885 301 LTCIICQDLLHDCVSLQPCMHTFCAACYSGWMeRSSL--CPTCRCPV 345
Cdd:cd16531    2 LMCPICLGIIKNTMTVKECLHRFCAECIEKAL-RLGNkeCPTCRKHL 47

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

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gi 564379885 302 TCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:cd16532    2 ICPICQDEFKDPVVL-RCKHIFCEDCVSEWFERERTCPLCR 41

Zinc finger, C3HC4 type (RING finger);

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gi 564379885  299 ETLTCIICQDLLHDCVsLQPCMHT-FCAACYSGWMERSSLCPTCRCPVERI 348
Cdd:pfam13920   1 EDLLCVICLDRPRNVV-LLPCGHLcLCEECAERLLRKKKKCPICRQPIESV 50

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.

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gi 564379885 302 TCIICQD--LLHDCVSLQPCMHTFCAACYSGWMERSSLCPTC 341
Cdd:cd16468    1 ECVICMAdfVVGDPIRYLPCMHIYHVDCIDDWLMRSFTCPSC 42

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 564379885 296 KMEETLTCIICQDLLHDCVSLQpCMHTFCAACYSGWMERSS---LCPTCRCPVER--ICKNHILNNLVEAYL 362
Cdd:cd16498   12 AMQKNLECPICLELLKEPVSTK-CDHQFCRFCILKLLQKKKkpaPCPLCKKSVTKrsLQESTRFKQLVEAVK 82

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.

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gi 564379885 303 CIICQDLLHDC--VSLQPCMHTFCAACYSGWME-RSSLCPTCR 342
Cdd:cd16448    1 CVICLEEFEEGdvVRLLPCGHVFHLACILRWLEsGNNTCPLCR 43

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 564379885 302 TCIICQDLLHDCVS-LQPCMHTFCAACYSGWMERSSLCPTCRCP 344
Cdd:cd16574    3 SCPICLDRFENEKAfLDGCFHAFCFTCILEWSKVKNECPLCKQP 46

RING finger, HC subclass, found in Mus musculus tripartite motif-containing protein 43 (TRIM43) and similar propteins; This subfamily includes TRIM43A, TRIM43B and TRIM43C, which are expressed specifically in mouse preimplantation embryos. They contain a typical C3HC4-type RING-HC finger.

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gi 564379885 298 EETLTCIICQDLLHDCVSLQpCMHTFCAACYSGWMERSSL---CPTCRCPV 345
Cdd:cd23133    1 EETLTCSICQGIFMNPVYLR-CGHKFCEACLLLFQEDIKFpayCPMCRQPF 50

Modified RING finger, HC subclass (C3HC3D-type), found in ligand of Numb protein LNX1, LNX2, and similar proteins; The ligand of Numb protein X (LNX) family, also known as PDZ and RING (PDZRN) family, includes LNX1-5, which can interact with Numb, a key regulator of neurogenesis and neuronal differentiation. LNX5 (also known as PDZK4 or PDZRN4L) shows high sequence homology to LNX3 and LNX4, but it lacks the RING domain. LNX1-4 proteins function as E3 ubiquitin ligases and have a unique domain architecture consisting of an N-terminal RING-HC finger for E3 ubiquitin ligase activity and either two or four PDZ domains necessary for substrate-binding. LNX1/LNX2-like proteins contain a modified C3HC3D-type RING-HC finger and four PDZ domains. This model corresponds to the RING finger.

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gi 564379885 301 LTCIICQDLLHDCVsLQPCMHTFCAACYSGWMERSSLCP 339
Cdd:cd16637    2 LTCHICLQPLVEPL-DTPCGHTFCYKCLTNYLKIQQCCP 39

second RING finger, HC subclass, found in the LON peptidase N-terminal domain and RING finger protein family; The LON peptidase N-terminal domain and RING finger protein family includes LONRF1 (also known as RING finger protein 191 or RNF191), LONRF2 (also known as RING finger protein 192, RNF192, or neuroblastoma apoptosis-related protease), LONRF3 (also known as RING finger protein 127 or RNF127), which are characterized by containing two C3HC4-type RING-HC fingers, four tetratricopeptide (TPR) repeats, and an ATP-dependent protease La (LON) substrate-binding domain at the C-terminus. Their biological functions remain unclear. This model corresponds to the second RING-HC finger.

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gi 564379885 301 LTCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSLCPTCRCPV 345
Cdd:cd16514    2 LECSLCLRLLYEPVTT-PCGHTFCRACLERCLDHSPKCPLCRTSL 45

RING finger, HC subclass, found in protein Deltex-3-like (DTX3L) and similar proteins; DTX3L, also known as B-lymphoma- and BAL-associated protein (BBAP) or Rhysin-2 (Rhysin2), is a RING-domain E3 ubiquitin-protein ligase that regulates endosomal sorting of the G protein-coupled receptor CXCR4 from endosomes to lysosomes. It also regulates subcellular localization of its partner protein, B aggressive lymphoma (BAL), by a dynamic nucleocytoplasmic trafficking mechanism. DTX3L has a unique N-terminus, but lacks the highly basic N-terminal motif and the central proline-rich motif present in other Deltex (DTX) family members, such as DTX1, DTX2, and DTX4. Moreover, its C-terminal region is highly homologous to DTX3. It includes a C3HC4-type RING-HC finger, and a previously unidentified C-terminal domain. DTX3L can associate with DTX1 through its unique N-terminus and further enhance self-ubiquitination.

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gi 564379885 298 EETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTC 341
Cdd:cd16712    1 QEEDECPICMDRISNKKVLPKCKHVFCAACIDKAMKYKPVCPVC 44

first RING finger, HC subclass, found in Arabidopsis thaliana ORTHRUS and similar proteins; This subfamily includes Arabidopsis thaliana ORTHRUS 1-5. They are E3 ubiquitin-protein ligases that may participate in CpG methylation-dependent transcriptional regulation and/or epigenetic transcriptional silencing. ORTHRUS 1 mediates ubiquitination with the E2 ubiquitin-conjugating enzymes UBC11, UBC8 and UBC8 homologs (e.g. UBC10, UBC11, UBC28 and UBC29) but not with UBC27, UBC30, UBC32, UBC34 and UBC36. ORTHRUS 2 and 5 mediate ubiquitination with the E2 ubiquitin-conjugating enzyme UBC11. ORTHRUS 1 and 2 promote methylation-mediated gene silencing leading, for example, to early flowering. They can bind to CpG, CpNpG, and CpNpN DNA motifs, with a strong preference for methylated forms, and with highest affinity for CpG substrates. Members of this subfamily contain two typical C3HC4-type RING-HC fingers. This model corresponds to the first one.

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gi 564379885 299 ETLTCIICQDLLHDCVSlQPCMHTFCAACYSGWMERSSL-CPTCRCPV 345
Cdd:cd23138    1 DELNCSFCMQLPERPVT-TPCGHNFCLKCFQKWMGQGKKtCGTCRSPI 47

RING finger, HC subclass, found in tripartite motif-containing protein 69 (TRIM69) and similar proteins; TRIM69, also known as RFP-like domain-containing protein trimless or RING finger protein 36 (RNF36), is a testis E3 ubiquitin-protein ligase that plays a specific role in apoptosis and may also play an important role in germ cell homeostasis during spermatogenesis. TRIM69 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 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.

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gi 564379885 297 MEEtLTCIICQDLLHDCVSLQpCMHTFCAACYSGWMERS---SLCPTCR--CPVERICKN 351
Cdd:cd16611    2 TEE-LHCPLCLDFFRDPVMLS-CGHNFCQSCITGFWELQaedTTCPECRelCQYRNLTPN 59