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 57164149   468 TTAPGYTCPLQGSHAICTCCFQPMPDRRAeheqdsRIAPQQCAVCLQPFCHLYW-GCTRTGCFGCLAPFcELNLGDKCLD 546
Cdd:pfam17979   6 TAIGGFQCPPQTQHLQCTCCGGMMPDRRD------AGVPQQCLLCKRPFCGLYWgGCPRAGCQGCLKPF-SENLISKIPD 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149   547 GVLNNNNYESDILKNYLTTRGLTWKNMLTESLLALQRGVFI-------LSDYRITGNTVLCYCCGLRSFRELTYQYRQNI 619
Cdd:pfam17979  79 NVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIDrtrkplnLSDYIITADTPLCNDCALKLFSFLLYKYRISI 158

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 57164149 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 57164149   631 RPDCYWGRNCRTQvKAHHAMKFNH 654
Cdd:pfam10283   1 RPPCKYGAKCYRK-NPQHFKEFSH 23

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 57164149   468 TTAPGYTCPLQGSHAICTCCFQPMPDRRAeheqdsRIAPQQCAVCLQPFCHLYW-GCTRTGCFGCLAPFcELNLGDKCLD 546
Cdd:pfam17979   6 TAIGGFQCPPQTQHLQCTCCGGMMPDRRD------AGVPQQCLLCKRPFCGLYWgGCPRAGCQGCLKPF-SENLISKIPD 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149   547 GVLNNNNYESDILKNYLTTRGLTWKNMLTESLLALQRGVFI-------LSDYRITGNTVLCYCCGLRSFRELTYQYRQNI 619
Cdd:pfam17979  79 NVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIDrtrkplnLSDYIITADTPLCNDCALKLFSFLLYKYRISI 158

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 57164149 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 57164149    38 WTIGRRRGCDLSFPSnKLVSGDHCKLRVDEkSGEVTLEDT-STNGTVINKLRvVKKQTYPLQSGDIIYL 105
Cdd:pfam00498   1 VTIGRSPDCDIVLDD-PSVSRRHAEIRYDG-GGRFYLEDLgSTNGTFVNGQR-LGPEPVRLKDGDVIRL 66

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 57164149   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 57164149    26 EDEPQILLWKREWTIGRRRGCDLSFPS-NKLVSGDHCKLRVDEksGEVTLEDTSTNGTVINKL--RVVKKQTYPLQSGDI 102
Cdd:TIGR03354  14 GIAAQKTFGTNGGTIGRSEDCDWVLPDpERHVSGRHARIRYRD--GAYLLTDLSTNGVFLNGSgsPLGRGNPVRLEQGDR 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149   103 IYL-------------VYRKNEPEHNVAYLYEslNGKQSLTQESLEANKENMFHVTKESSGPGQGDDPQVPLLSPMAQTc 169
Cdd:TIGR03354  92 LRLgdyeirvslgdplVSRQASESRADTSLPT--AGGPPTPDPAPLAQLDPLKALDQEPLSAADLDDLSAPLFPPLDAR- 168

                         170       180
                  ....*....|....*....|....*.
gi 57164149   170 leepQPststSDLLPTASTSSTEPEL 195
Cdd:TIGR03354 169 ----LP----AFAAPIDAEPTMVPPF 186

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149 229 SLSSVFQDNEASFS-LLKTEDTEELEPAKKK----------MKGDGELDLNLQLSVADQRGIAQTSSEDVKDASVKPDKM 297
Cdd:COG5574 133 DLKQTANTHEASPSqLLKFLPTIRLAMNIPEvisdltavalSLDESRLQPILQPSNNLHTLFQVITKENLSKKNGLPFIP 212

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 57164149 298 EETLTCIICQDLLHdCVSLQPCMHTFCAAC-YSGWMERSSL-CPTCR 342
Cdd:COG5574 213 LADYKCFLCLEEPE-VPSCTPCGHLFCLSClLISWTKKKYEfCPLCR 258

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 57164149     38 WTIGRRR-GCDLSFPSNKlVSGDHCKLRVDEKsGEVTLEDT-STNGTVINKLRV 89
Cdd:smart00240   1 VTIGRSSeDCDIQLDGPS-ISRRHAVIVYDGG-GRFYLIDLgSTNGTFVNGKRI 52

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 57164149   468 TTAPGYTCPLQGSHAICTCCFQPMPDRRAeheqdsRIAPQQCAVCLQPFCHLYW-GCTRTGCFGCLAPFcELNLGDKCLD 546
Cdd:pfam17979   6 TAIGGFQCPPQTQHLQCTCCGGMMPDRRD------AGVPQQCLLCKRPFCGLYWgGCPRAGCQGCLKPF-SENLISKIPD 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149   547 GVLNNNNYESDILKNYLTTRGLTWKNMLTESLLALQRGVFI-------LSDYRITGNTVLCYCCGLRSFRELTYQYRQNI 619
Cdd:pfam17979  79 NVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIDrtrkplnLSDYIITADTPLCNDCALKLFSFLLYKYRISI 158

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 57164149 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 57164149  18 RLLRLGAEEDEPQILLWKREWTIGRRRGCDLSFPsNKLVSGDHCKLRVDEksGEVTLEDT-STNGTVINKLRVVKKqtYP 96
Cdd:cd00060   1 RLIVLDGDGGGREFPLTKGVVTIGRSPDCDIVLD-DPSVSRRHARIEVDG--GGVYLEDLgSTNGTFVNGKRITPP--VP 75

                ....*....
gi 57164149  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 57164149    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 57164149  39 TIGRRRGCDLSFP-SNKLVSGDHCKLRVDEksGEVTLEDTSTNGTVIN--KLRVVKKQTYPLQSGDII----Y--LVYRK 109
Cdd:COG3456  29 TIGRSADCDWVLPdPDRSVSRRHAEIRFRD--GAFCLTDLSTNGTFLNgsDHPLGPGRPVRLRDGDRLrigdYeiRVEIS 106

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149 110 NEPEHNVAYLYEslngkQSLTQESLEANKENMFHVTKESSGPGQGDDPQVPLLSPMAqtclEEPQPSTSTSDLLPTASTS 189
Cdd:COG3456 107 GEDEGADDPLAA-----APEPAVSSPSNLSDTEAAPDAALAFSFSLDPLEALDEAAT----EAPATADDPPSLLPEDWLP 177

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 57164149 190 STEPeltSAGQKHSSSSGPGTISISPKECSSLVANGELSSLSSVFQDNEASFSLLKTEDTEEL 252
Cdd:COG3456 178 SAAP---VADEAAAQAIDQLPSAAAPAPEPEPAADADHALLAALLRGLGLDLELLDSQDAEDF 237

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
                ....*....|....*....|....*....|....*....|....*.
gi 57164149 303 CIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTCRCPVERI 348
Cdd:cd23130   3 CPICLDDPEDEAITLPCLHQFCYTCILRWLQTSPTCPLCKTPVTSI 48

first forkhead associated (FHA) domain found in Saccharomyces cerevisiae Serine/threonine-protein kinase RAD53 and similar proteins; RAD53, also called CHEK2 homolog, or serine-protein kinase 1 (Spk1), is a nuclear protein kinase that phosphorylates proteins on serine, threonine, and tyrosine. It controls S-phase checkpoint as well as G1 and G2 DNA damage checkpoints and prevents entry into anaphase and mitotic exit after DNA damage via regulation of the Polo kinase CDC5. It may be involved in the phosphorylation of RPH1. RAD53 contains two FHA domains. This model corresponds to the first one. The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149   9 QPPPREPWGRLLRLGAEEDEPqillwKREWTIGRRRGCDLSFpSNKLVSGDHCKL---RVDEKSGEVTLEDTSTNGTVIN 85
Cdd:cd22689  23 QEPIRDLSGDISQVLKEKRSI-----KKVWTFGRHPACDYHL-GNSRLSNKHFQIllgESDPSDGNVLLNDISSNGTWLN 96

                        90       100
                ....*....|....*....|
gi 57164149  86 KLRVVKKQTYPLQSGDIIYL 105
Cdd:cd22689  97 GQRLEKNSNQLLSQGDEITI 116

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 57164149  17 GRLLRLGAEEDEPQI-LLWKREWTIGRRRGCDLSFpSNKLVSGDHCKLRVdEKSGEVTLEDTSTNGTVINKLRVVKKqTY 95
Cdd:cd22683   1 GSLVNLIVG*KEQKIsITNRNVTTIGRSRSCDLVL-SDPSISRFHAELRL-EQNGINVIDNNSANGTFINGKRIKGK-TY 77

                        90
                ....*....|
gi 57164149  96 PLQSGDIIYL 105
Cdd:cd22683  78 ILKNGDIIVF 87

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 57164149 297 MEETLTCIICQDLLHDCVSLqPCMHTFCAACYSG-WME---RSSLCPTCRCPVER---ICKNHILNNLVE 359
Cdd:cd16597   2 LEEELTCSICLELFKDPVTL-PCGHNFCGVCIEKtWDSqhgSEYSCPQCRATFPRrpeLHKNTVLRNIVE 70

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 57164149   302 TCIICQDLL--HDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:pfam13639   2 ECPICLEEFeeGDKVVVLPCGHHFHRECLDKWLRSSNTCPLCR 44

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 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
                ....*....|....*....|....*....|....*....|....*....|...
gi 57164149 298 EETLTCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSL----CPTCRCPVE 346
Cdd:cd16609   1 EEELTCSICLGLYQDPVTL-PCQHSFCRACIEDHWRQKDEgsfsCPECRAPFP 52

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 57164149 299 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSL-CPTCRCPV 345
Cdd:cd16544   1 AELTCPVCQEVLKDPVELPPCRHIFCKACILLALRSSGArCPLCRGPV 48

forkhead associated (FHA) domain found in Myxococcus xanthus EspA and similar proteins; EspA is a histidine protein kinase with a fork head-associated (FHA) domain at the N-terminus and a receiver domain at the C-terminus. It functions as an inhibitor of sporulation during early fruiting body development while cells are aggregating into raised mounds. EspA is part of a two-component signal transduction system that regulates the timing of sporulation initiation. The FHA domain is a small phosphopeptide recognition module.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57164149  22 LGAEEDEPqILLWKREWTIGRRRGCDLSFPSNKlVSGDHCklRVDEKSGEVTLEDT-STNGTVINKLRVvkkQTYPLQSG 100
Cdd:cd22698   8 KGSEEGKD-YELDQDEFTIGRSSNNDIRLNDHS-VSRHHA--RIVRQGDKCNLTDLgSTNGTFLNGIRV---GTHELKHG 80

                ....*
gi 57164149 101 DIIYL 105
Cdd:cd22698  81 DRIQL 85

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 57164149 302 TCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:cd16479   3 TCIICREEMTVGAKKLPCGHIFHLSCLRSWLQRQQTCPTCR 43

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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 57164149  38 WTIGRRRGCDLSF--PSnklVSGDHCKL----RVDEKSGEVTLEDT-STNGTVINKLRVVKKQTYPLQSGDII 103
Cdd:cd22677  24 YVFGRLPGCDVVLehPS---ISRYHAVLqyrgDADDHDGGFYLYDLgSTHGTFLNKQRIPPKQYYRLRVGHVL 93

HC subclass of RING (RING-HC) finger 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 a different Cys/His pattern. Some lack a single Cys or His residue at typical Zn ligand positions, especially, the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can chelate Zn in a RING finger as well. This family corresponds to the HC subclass of RING (RING-HC) fingers that are characterized by containing C3HC4-type canonical RING-HC fingers or noncanonical RING-HC finger variants, including C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type modified RING-HC fingers. The canonical RING-HC finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-HC fingers 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 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 enables efficient transfer of ubiquitin from E2 to the substrates.

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                ....*....|....*....|....*....|....*....|..
gi 57164149 301 LTCIICQDLLHDCVSLqPCMHTFCAACYSGWME-RSSLCPTC 341
Cdd:cd16449   1 LECPICLERLKDPVLL-PCGHVFCRECIRRLLEsGSIKCPIC 41

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 57164149 302 TCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:cd16532   2 ICPICQDEFKDPVVL-RCKHIFCEDCVSEWFERERTCPLCR 41

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 57164149 302 TCIICQD--LLHDCVSLQPCMHTFCAACYSGWMERSSLCPTC 341
Cdd:cd16468   1 ECVICMAdfVVGDPIRYLPCMHIYHVDCIDDWLMRSFTCPSC 42

RING finger, HC subclass, found in Saccharomyces cerevisiae POB3/SPT16 histone-associated protein 1 (ScPSH1) and similar proteins; ScPSH1 is a Cse4-specific E3 ubiquitin ligase that interacts with the kinetochore protein Pat1 and targets the degradation of budding yeast centromeric histone H3 variant, CENP-ACse4, which is essential for faithful chromosome segregation. ScPSH1 contains a C3HC4-type RING-HC finger and a DNA directed RNA polymerase domain.

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                ....*....|....*....|....*....|....*....|....*....|....
gi 57164149 297 MEETLTCIICQDLLHDCVSLqPCMHTFCAACYSGWM--ERSSLCPTCRCPVERI 348
Cdd:cd16568   1 ILETQECIICHEYLYEPMVT-TCGHTYCYTCLNTWFksNRSLSCPDCRTKITTQ 53

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 57164149 303 CIICQDLLHDC--VSLQPCMHTFCAACYSGWME-RSSLCPTCR 342
Cdd:cd16448   1 CVICLEEFEEGdvVRLLPCGHVFHLACILRWLEsGNNTCPLCR 43

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 57164149 302 TCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSL-CPTCR 342
Cdd:cd16550   2 LCPICLEILVEPVTL-PCNHTLCMPCFQSTVEKASLcCPLCR 42

RING finger found in polycomb group RING finger protein 3 (PCGF3) and similar proteins; PCGF3, also known as RING finger protein 3A (RNF3A), is one of six PcG RING finger (PCGF) homologs (PCGF1, PCGF2/Mel-18, PCGF3, PCGF4/BMI1, PCGF5, and PCGF6) and serves as the core component of a Polycomb repressive complex 1 (PRC1). Like other PCGF homologs, PCGF3 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. PCGF3 contains a C3HC4-type RING-HC finger.

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                ....*....|....*....|....*....|....*....|..
gi 57164149 301 LTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:cd16735  12 ITCRLCKGYLIDATTITECLHTFCKSCLVKYLEENNTCPTCG 53

RING finger, HC subclass, found in polycomb group RING finger protein 1 (PCGF1) and similar proteins; PCGF1, also known as nervous system Polycomb-1 (NSPc1) or RING finger protein 68 (RNF68), 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 noncanonical Polycomb repressive complex 1 (PRC1)-like BCOR complex that also contains RING1, RNF2, RYBP, SKP1, as well as the BCL6 co-repressor BCOR and the histone demethylase KDM2B, and is required to maintain the transcriptionally repressive state of some genes, such as Hox genes, BCL6 and the cyclin-dependent kinase inhibitor, CDKN1A. PCGF1 promotes cell cycle progression and enhances cell proliferation as well. It is a cell growth regulator that acts as a transcriptional repressor of p21Waf1/Cip1 via the retinoid acid response element (RARE element). Moreover, PCGF1 functions as an epigenetic regulator involved in hematopoietic cell differentiation. It cooperates with the transcription factor runt-related transcription factor 1 (Runx1) in regulating differentiation and self-renewal of hematopoietic cells. Furthermore, PCGF1 represents a physical and functional link between Polycomb function and pluripotency. PCGF1 contains a C3HC4-type RING-HC finger.

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                ....*....|....*....|....*....|....*....|....*....|
gi 57164149 292 VKPDKMEETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTC 341
Cdd:cd16733   1 VKIKDLNEHIVCYLCAGYFIDATTITECLHTFCKSCIVKYLQTSKYCPMC 50

RING finger, HC subclass, found in Arabidopsis thaliana protein BREAST CANCER SUSCEPTIBILITY 1 homolog (AtBRCA1) and similar proteins; AtBRCA1 plays a role in DNA repair and in cell-cycle control. It is required for the repair of DNA double-strand breaks (DSBs), both natural and induced by genotoxic stress, by homologous recombination (HR). AtBRCA1 contains a typical C3HC4-type RING-HC finger.

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                ....*....|....*....|....*....|....*....|....*..
gi 57164149 301 LTCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSLCPTCRCPVER 347
Cdd:cd23147   5 LKCPICLSLFKSAANL-SCNHCFCAGCIGESLKLSAICPVCKIPATR 50

RING finger, HC subclass, found in Polycomb Group RING finger homologs (PCGF1, 2, 3, 4, 5 and 6), and similar proteins; This subfamily includes six Polycomb Group (PcG) RING finger homologs (PCGF1/NSPc1, PCGF2/Mel-18, PCGF3, PCGF4/BMI1, PCGF5, and PCGF6/MBLR) that use epigenetic mechanisms to maintain or repress expression of their target genes. They were first discovered in fruit flies and are well known for silencing Hox genes through modulation of chromatin structure during embryonic development. PCGF homologs play important roles in cell proliferation, differentiation, and tumorigenesis. They all have been found to associate with ring finger protein 2 (RNF2). The RNF2-PCGF heterodimer is catalytically competent as an E3 ubiquitin transferase and is the scaffold for the assembly of additional components. Moreover, PCGF homologs are critical components in the assembly of distinct Polycomb Repression Complex 1 (PRC1) related complexes which is involved in the maintenance of gene repression and which target different genes through distinct mechanisms. The Drosophila PRC1 core complex is formed by the Polycomb (Pc), Polyhomeotic (Ph), Posterior sex combs (Psc), and Sex combs extra (Sce, also known as Ring) subunits. In mammals, the composition of PRC1 is much more diverse and varies depending on the cellular context. All PRC1 complexes contain homologs of the Drosophila Ring protein. Ring1A/RNF1 and Ring1B/RNF2 are E3 ubiquitin ligases that mark lysine 119 of histone H2A with a single ubiquitin group (H2AK119ub). Mammalian homologs of the Drosophila Psc protein, such as PCGF2/Mel-18 or PCGF4/BMI1, regulate PRC1 enzymatic activity. PRC1 complexes can be divided into at least two classes according to the presence or absence of CBX proteins, which are homologs of Drosophila Pc. Canonical PRC1 complexes contain CBX proteins that recognize and bind H3K27me3, the mark deposited by PRC2. Therefore, canonical PRC1 complexes and PRC2 can act together to repress gene transcription and maintain this repression through cell division. Non-canonical PRC1 complexes, containing RYBP (together with additional proteins, such as L3mbtl2 or Kdm2b) rather than the CBX proteins have recently been described in mammals. PCGF homologs contain a C3HC4-type RING-HC finger.

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gi 57164149 301 LTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 342
Cdd:cd16525   1 LTCSLCKGYLIDATTITECLHSFCKSCIVRHLETSKNCPVCD 42