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 239048905  452 SVSLTTAVQDYVCPLQGSHALCTCCFQPMPDRRaereqdPRVAPQQCAVCLQPFCHLYW-GCTRTGCYGCLAPFcELNLG 530
Cdd:pfam17979   1 CPQCGTAIGGFQCPPQTQHLQCTCCGGMMPDRR------DAGVPQQCLLCKRPFCGLYWgGCPRAGCQGCLKPF-SENLI 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  531 DKCLDGVLNNNSYESDILKNYLATRGLTWKNMLTESLVALQRGVF-------LLSDYRVTGDTVLCYCCGLRSFRELTYQ 603
Cdd:pfam17979  74 SKIPDNVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIdrtrkplNLSDYIITADTPLCNDCALKLFSFLLYK 153

                  ....*
gi 239048905  604 YRQNI 608
Cdd:pfam17979 154 YRISI 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 239048905 288 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSS-LCPTCRCPVERICKNH 341
Cdd:cd16503    1 ENLTCSICQDLLHDCVSLQPCMHNFCAACYSDWMERSNtECPTCRATVQRVNKNH 55

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  286 MEETLTCIICQDLLHDCVsLQPCMHTFCAACYSGWMERSSLCPTCRCPVE--RICKNHILNNLVEAYLIQHPDKSRSEED 363
Cdd:TIGR00599  23 LDTSLRCHICKDFFDVPV-LTSCSHTFCSLCIRRCLSNQPKCPLCRAEDQesKLRSNWLVSEIVESFKNLRPSLLEFLRI 101

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  364 VQSMDARNKITQDMLQPKVRRSFSDEEGSSEDLLELSDVDSESSDisqpyvvcrqcpeyRRQAAQPPHCPAPEGEPGAPQ 443
Cdd:TIGR00599 102 PKTTPVENPDLAGPENSSKIELIEESESDGVDAEDEDLQRSATSS--------------RALAARSTADILQLSSDPSKR 167

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 239048905  444 ALGDAPSTsvslttavqdyvcPLQGSHALCTCCFQPMPDRRAEREQD 490
Cdd:TIGR00599 168 NDADYRSE-------------PPNEGLVQCPICQQRMPEKAVERHLD 201

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 239048905  452 SVSLTTAVQDYVCPLQGSHALCTCCFQPMPDRRaereqdPRVAPQQCAVCLQPFCHLYW-GCTRTGCYGCLAPFcELNLG 530
Cdd:pfam17979   1 CPQCGTAIGGFQCPPQTQHLQCTCCGGMMPDRR------DAGVPQQCLLCKRPFCGLYWgGCPRAGCQGCLKPF-SENLI 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  531 DKCLDGVLNNNSYESDILKNYLATRGLTWKNMLTESLVALQRGVF-------LLSDYRVTGDTVLCYCCGLRSFRELTYQ 603
Cdd:pfam17979  74 SKIPDNVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIdrtrkplNLSDYIITADTPLCNDCALKLFSFLLYK 153

                  ....*
gi 239048905  604 YRQNI 608
Cdd:pfam17979 154 YRISI 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 239048905 288 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSS-LCPTCRCPVERICKNH 341
Cdd:cd16503    1 ENLTCSICQDLLHDCVSLQPCMHNFCAACYSDWMERSNtECPTCRATVQRVNKNH 55

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 239048905   38 WTIGRRRGCDLSFPSnKLVSGDHCRIVVDEkSGQVTLEDT-STSGTVINKlKVVKKQTCPLQTGDVIYL 105
Cdd:pfam00498   1 VTIGRSPDCDIVLDD-PSVSRRHAEIRYDG-GGRFYLEDLgSTNGTFVNG-QRLGPEPVRLKDGDVIRL 66

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 239048905  291 TCIICQDLL--HDCVSLQPCMHTFCAACYSGWMERSSLCPTCR 331
Cdd:pfam13639   2 ECPICLEEFeeGDKVVVLPCGHHFHRECLDKWLRSSNTCPLCR 44

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 239048905   292 CIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSL-CPTC 330
Cdd:smart00184   1 CPICLEEYLKDPVILPCGHTFCRSCIRKWLESGNNtCPIC 40

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905 286 MEETLTCIICQDLLHDCVsLQPCMHTFCAACYSGWMERSSLCPTCRCPVE--RICKNHILNNLVEAYLIQHPdksrSEED 363
Cdd:COG5432   22 LDSMLRCRICDCRISIPC-ETTCGHTFCSLCIRRHLGTQPFCPVCREDPCesRLRGSSGSREINESHARNRD----LLRK 96

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 239048905 364 VQSMDARNKITQDMLQPKVRRSFSDEEGSSEDLLELSDVDSESSDISQPYVVCRQCpeYRRQAAQPPHCPA 434
Cdd:COG5432   97 VLESLCRLPRPIKEERPCRWETVIAQDSASGDEEWEDDLASNSSPASIAKKTSRDS--KKRKREDLVHCPA 165

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 239048905  620 RPDCYWGRNCRTQvKAHHAMKFNH 643
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 239048905  452 SVSLTTAVQDYVCPLQGSHALCTCCFQPMPDRRaereqdPRVAPQQCAVCLQPFCHLYW-GCTRTGCYGCLAPFcELNLG 530
Cdd:pfam17979   1 CPQCGTAIGGFQCPPQTQHLQCTCCGGMMPDRR------DAGVPQQCLLCKRPFCGLYWgGCPRAGCQGCLKPF-SENLI 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  531 DKCLDGVLNNNSYESDILKNYLATRGLTWKNMLTESLVALQRGVF-------LLSDYRVTGDTVLCYCCGLRSFRELTYQ 603
Cdd:pfam17979  74 SKIPDNVFNGNQYEQDILQDYLAQKGKTLQDVISEWLQKLDNGEIdrtrkplNLSDYIITADTPLCNDCALKLFSFLLYK 153

                  ....*
gi 239048905  604 YRQNI 608
Cdd:pfam17979 154 YRISI 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 239048905 288 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSS-LCPTCRCPVERICKNH 341
Cdd:cd16503    1 ENLTCSICQDLLHDCVSLQPCMHNFCAACYSDWMERSNtECPTCRATVQRVNKNH 55

second 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 second one. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  16 WGRLLRLGaeEGEPHVLLRKREWTIGRRRGCDLSFPSNKlVSGDHCRIVVDEKS---GQVTLEDTSTSGTVINKLKVVKK 92
Cdd:cd22690    1 WGRLKSLN--PSYPDIELTQNTTFIGRSKDCDEEITDPR-ISKHHCIITRKRSGkglDDVYVTDTSTNGTFINNNRLGKG 77

                         90       100
                 ....*....|....*....|....*....
gi 239048905  93 QTCPLQTGDVIYLVYRKNEPEHnVAYLYE 121
Cdd:cd22690   78 SQSLLQDGDEIVLIWDKNNKEK-IGFIFQ 105

forkhead associated (FHA) domain found in checkpoint kinase 2 (Chk2) and similar proteins; Chk2, also called Hucds1, Cds1 homolog, or serine/threonine-protein kinase Chk2, plays an important role in cellular responses to DNA double-strand breaks and related lesions. It is phosphorylated and activated by ATM kinase, resulting in its dissociation from sites of damage to phosphorylate downstream targets such as BRCA1, p53, cell cycle transcription factor E2F1, the promyelocytic leukemia protein (PML) involved in apoptosis, and CDC25 phosphatases, among others. Mutations in Chk2 is linked to a variety of cancers including familial breast cancer, myelodysplastic syndromes, prostate cancer, lung cancer, and osteosarcomas. Chk2 contains an N-terminal SQ/TQ cluster domain (SCD), a central forkhead-associated (FHA) domain, and a C-terminal catalytic kinase domain. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  16 WGRLLRLGAeeGEPHVLLRKREWTIGRRRGCDLSFPSNKLVSGD--------HCRIVVDEKSG---QVTLEDTSTSGTVI 84
Cdd:cd22666    1 WGRLFPLGS--GFSSLDLVKDEYTFGRDKSCDYCFDSPALKKTSyyrtyskkHFRIFREKGSKntyPVFLEDHSSNGTFV 78

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 239048905  85 NKLKVVKKQTCPLQTGDVIYLVYRKNEpehnvAYLYESL 123
Cdd:cd22666   79 NGEKIGKGKKRPLNNNDEIALSLPKNK-----VFVFMDL 112

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 239048905  31 VLLRKREWTIGRRRGCDLSFP-SNKLVSGDHCRIVVDEksGQVTLEDTSTSGTVIN--KLKVVKKQTCPLQTGDVI---- 103
Cdd:COG3456   21 ATFGRGGGTIGRSADCDWVLPdPDRSVSRRHAEIRFRD--GAFCLTDLSTNGTFLNgsDHPLGPGRPVRLRDGDRLrigd 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905 104 Y--LVYRKNEPEHNVAYLYESLSEKQGMTQESFDTSGA-----GAGRGADPRVPPSSPATqvcfeePQPSTSTSDLFPTA 176
Cdd:COG3456   99 YeiRVEISGEDEGADDPLAAAPEPAVSSPSNLSDTEAApdaalAFSFSLDPLEALDEAAT------EAPATADDPPSLLP 172

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 239048905 177 SASSTEPSPAGRERSSSCGSGGGGISPKGSGPSVASDEVSSFASALPDRKTASFSSLEPQDQEDL 241
Cdd:COG3456  173 EDWLPSAAPVADEAAAQAIDQLPSAAAPAPEPEPAADADHALLAALLRGLGLDLELLDSQDAEDF 237

forkhead associated (FHA) domain found in Saccharomyces cerevisiae meiosis-specific serine/threonine-protein kinase MEK1 and similar proteins; MEK1 (EC 2.7.11.1), also known as MRE4, is a meiosis-specific protein kinase required for chromosome synapsis and meiotic recombination. The recruitment and activation of MEK1 require the phosphorylation of the chromosome axis protein Hop1 at Thr318 (pT318), which is necessary for recognition by the MEK1 FHA domain. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 239048905  32 LLRKREWTIGRRRGCDLSFPsNKLVSGDHCRI---VVDEKSGQVT-LEDTSTSGTVINKLKVVKKQTCPLQTGDVIYL 105
Cdd:cd22670   18 IYKNQVITIGRSPSCDIVIN-DPFVSRTHCRIysvQFDESSAPLVyVEDLSSNGTYLNGKLIGRNNTVLLSDGDVIEI 94

forkhead associated (FHA) domain found in nibrin and similar proteins; Nibrin (NBN), also called cell cycle regulatory protein p95, or Nijmegen breakage syndrome protein 1 (NBS1), is a novel DNA double-strand break repair protein that is mutated in Nijmegen breakage syndrome. It is a component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. Nibrin modulates the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. Nibrin also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. Nibrin is a major player in the control of intra-S-phase checkpoint. This subfamily also includes Schizosaccharomyces pombe DNA repair and telomere maintenance protein Nbs1 and Arabidopsis thaliana AtNbs1. SpNbs1 is an FHA domain-containing protein required for DNA damage repair and S-phase DNA damage checkpoint. It is involved in telomere length maintenance and maintenance of chromatin structure. AtNbs1 is a component of MRN complex. It also functions in the very early stages of meiosis. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 239048905  18 RLLRLGAEEGEPHVLLRKREWTIGRRrGCDLSFPSNKLVSGDHCRIVVDEKSG---------QVTLEDTSTSGTVINKLK 88
Cdd:cd22667    2 WLLSEQDGAGTSYYLLPGGEYTVGRK-DCDIIIVDDSSISRKHATLTVLHPEAnlsdpdtrpELTLKDLSKYGTFVNGEK 80

                         90
                 ....*....|....*
gi 239048905  89 VVKKQTCPLQTGDVI 103
Cdd:cd22667   81 LKGGSEVTLKDGDVI 95

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 239048905 286 MEETLTCIICQDLLHDCVSLqPCMHTFCAACYSG-WME---RSSLCPTCRCPVER---ICKNHILNNLVE 348
Cdd:cd16597    2 LEEELTCSICLELFKDPVTL-PCGHNFCGVCIEKtWDSqhgSEYSCPQCRATFPRrpeLHKNTVLRNIVE 70

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 239048905  32 LLRKREWTIGRRRGCDLSFPsNKLVSGDHCRIVVDekSGQVTLEDT-STSGTVINKLKVVKKQTCPLQTGDVI 103
Cdd:cd22682   16 PITESTIVIGRSVESQVQID-DDSVSRYHAKLAVN--PSAVSIIDLgSTNGTIVNGKKIPKLASCDLQNGDQI 85

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 239048905  35 KREWTIGRRRGCDLSFpSNKLVSGDHCRIVV---DEKSGQVTLEDTSTSGTVINKLKVVKKQTCPLQTGDVIYL 105
Cdd:cd22689   44 KKVWTFGRHPACDYHL-GNSRLSNKHFQILLgesDPSDGNVLLNDISSNGTWLNGQRLEKNSNQLLSQGDEITI 116

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 239048905 288 ETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSL-CPTCRCPV 334
Cdd:cd16544    1 AELTCPVCQEVLKDPVELPPCRHIFCKACILLALRSSGArCPLCRGPV 48

Zinc finger, C3HC4 type (RING finger);

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 239048905  292 CIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTC 330
Cdd:pfam13923   2 CPICMDMLKDPSTTTPCGHVFCQDCILRALEASNECPLC 40

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 239048905  38 WTIGRRRGCDLSF--PSnklVSGDHC----RIVVDEKSGQVTLEDT-STSGTVINKLKVVKKQTCPLQTGDVI 103
Cdd:cd22677   24 YVFGRLPGCDVVLehPS---ISRYHAvlqyRGDADDHDGGFYLYDLgSTHGTFLNKQRIPPKQYYRLRVGHVL 93

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 239048905  18 RLLRLGAEEGEPHV--LLRKR----EWTIGRRRG-CDLSFPSN---KLVSGDHCRIVV---DEKSGQVTLEDTSTSGTVI 84
Cdd:cd22685    4 QLLRIGLSASRSEPrdLYTFRpdlcEYRIGRNPEvCDVFLCSSqhpNLISREHAEIHAerdGNGNWKVLIEDRSTNGTYV 83

                         90
                 ....*....|....*....
gi 239048905  85 NKLKVVKKQTCPLQTGDVI 103
Cdd:cd22685   84 NDVRLQDGQRRELSDGDTI 102

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
                 ....*....|....*....|....*....|....*....|....*..
gi 239048905 290 LTCIICQDLLHDCVSLQPCMHTFCAACYSGWMeRSSL--CPTCRCPV 334
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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 239048905 291 TCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSLCPTCR 331
Cdd:cd16532    2 ICPICQDEFKDPVVL-RCKHIFCEDCVSEWFERERTCPLCR 41

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 239048905  288 ETLTCIICQDLLHDCVsLQPCMHT-FCAACYSGWMERSSLCPTCRCPVERI 337
Cdd:pfam13920   1 EDLLCVICLDRPRNVV-LLPCGHLcLCEECAERLLRKKKKCPICRQPIESV 50

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 239048905   292 CIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSL-CPTC 330
Cdd:smart00184   1 CPICLEEYLKDPVILPCGHTFCRSCIRKWLESGNNtCPIC 40

H2 subclass of RING (RING-H2) fingers and its variants; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). This family corresponds to the H2 subclass of RING (RING-H2) finger proteins that are characterized by containing C3H2C3-type canonical RING-H2 fingers or noncanonical RING-H2 finger variants, including C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type modified RING-H2 fingers. The canonical RING-H2 finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-H-X2-C-X(4-48)-C-X2-C, X is any amino acid and the number of X residues varies in different fingers. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-H2 finger can be found in a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serves as a scaffold for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enables efficient transfer of ubiquitin from E2 to the substrates.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|...
gi 239048905 292 CIICQDLLHDC--VSLQPCMHTFCAACYSGWME-RSSLCPTCR 331
Cdd:cd16448    1 CVICLEEFEEGdvVRLLPCGHVFHLACILRWLEsGNNTCPLCR 43

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 239048905  18 RLLRLGaEEGEPHVLL--RKREWTIGRRRG--CDLSFPSNKLVSGDHCRIVVDEkSGQVTLED-TSTSGTVINKLKVVKK 92
Cdd:cd22663    2 CLRRVG-HGIDPLVLLleDGKEVTVGRGLGvtYQLVSTCPLMISRNHCVLKKND-EGQWTIKDnKSLNGVWVNGERIEPL 79

                         90
                 ....*....|...
gi 239048905  93 QTCPLQTGDVIYL 105
Cdd:cd22663   80 KPYPLNEGDLIQL 92

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 239048905 291 TCIICQDLLHDCVSLqPCMHTFCAACYSGWMERSSL-CPTCR 331
Cdd:cd16550    2 LCPICLEILVEPVTL-PCNHTLCMPCFQSTVEKASLcCPLCR 42

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.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 239048905 290 LTCIICQDLLHDCVsLQPCMHTFCAACYSGWMERSSLCP 328
Cdd:cd16637    2 LTCHICLQPLVEPL-DTPCGHTFCYKCLTNYLKIQQCCP 39

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 239048905 286 MEETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTC 330
Cdd:cd16733    6 LNEHIVCYLCAGYFIDATTITECLHTFCKSCIVKYLQTSKYCPMC 50

RING finger, HC subclass, found in postreplication repair protein RAD18 and similar proteins; RAD18, also known as HR18 or RING finger protein 73 (RNF73), is an E3 ubiquitin-protein ligase involved in post replication repair of UV-damaged DNA via its recruitment to stalled replication forks. It associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on K164. It also interacts with another E2 ubiquitin conjugating enzyme RAD6 to form a complex that monoubiquitinates proliferating cell nuclear antigen at stalled replication forks in DNA translesion synthesis. Moreover, Rad18 is a key factor in double-strand break DNA damage response (DDR) pathways via its association with K63-linked polyubiquitylated chromatin proteins. It can function as a mediator for DNA damage response signals to activate the G2/M checkpoint in order to maintain genome integrity and cell survival after ionizing radiation (IR) exposure. RAD18 contains a C3HC4-type RING-HC finger, a ubiquitin-binding zinc finger domain (UBZ), a SAP (SAF-A/B, Acinus and PIAS) domain, and a RAD6-binding domain (R6BD).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 239048905 286 MEETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTCRCPV 334
Cdd:cd16529    1 LDDLLRCPICFEYFNTAMMITQCSHNYCSLCIRRFLSYKTQCPTCRAAV 49

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 239048905 287 EETLTCIICQDLLHDCVSLQPCMHTFCAACYSGWMERSSLCPTC 330
Cdd:cd16712    1 QEEDECPICMDRISNKKVLPKCKHVFCAACIDKAMKYKPVCPVC 44