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 564350724   2 RVCWLVRQDCWHQRIKLPHLEAVVIGRSPETKITDKKCSRQQVQLKAECNKRYVNVKQMGVNPTSIDEVVIGKDREMKLL 81
Cdd:cd22735    1 RVCWLVSKDGRHLRIRLPHLEAVVIGRGPETKITDKKCSRHQVQLKADCNKGYVKVKQLGVNPTSIDLVDIGKDEEVKLK 80

                         90       100
                 ....*....|....*....|
gi 564350724  82 PGQVLHMVNELYPYMVEFEE 101
Cdd:cd22735   81 PGQVLHIVNQLYPYIVEFEE 100

C2HE / C2H2 / C2HC zinc-binding finger; zf-C2HE is an unusual zinc-binding domain found in fungi, plants and metazoa. It is often found at the C-terminus of HIT-domain-containing proteins, pfam01230. In fungi the fourth ligand is a Glu, in plants it is Cys and in metazoans it is usually a His. The fourth ligand is often mutated in neurogenerative disease-states.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 564350724  270 NTEYFLESQAVIKMVQEAGRVTVKDGTCELLKLPLRCHECQQLLPSIPQLKEHLRKHW 327
Cdd:pfam16278   1 NTPFFVPLDDVPEWLEEDGKIELLPSEVLLLKTPLKCHRCGNFGNNFPKLKAHLEEHF 58

forkhead associated (FHA) domain found in aprataxin and similar proteins; Aprataxin (EC 3.6.1.71/EC 3.6.1.72), also called forkhead-associated domain histidine triad-like protein (FHA-HIT), is a DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair, and base excision repair. It catalyzes the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined. It can also hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity. Likewise, it catalyzes the release of 3'-linked guanosine (DNAppG) and inosine (DNAppI) from DNA but has higher specific activity with 5'-linked adenosine (AppDNA). Mutations in the gene APTX have been associated with ataxia-ocular apraxia. Aprataxin contains an FHA domain at its N-terminus. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724   2 RVCWLVRQDCWHQRIKLPHLEAVVIGRSPETKITDKKCSRQQVQLKAECNKRYVNVKQMGVNPTSIDEVVIGKDREMKLL 81
Cdd:cd22735    1 RVCWLVSKDGRHLRIRLPHLEAVVIGRGPETKITDKKCSRHQVQLKADCNKGYVKVKQLGVNPTSIDLVDIGKDEEVKLK 80

                         90       100
                 ....*....|....*....|
gi 564350724  82 PGQVLHMVNELYPYMVEFEE 101
Cdd:cd22735   81 PGQVLHIVNQLYPYIVEFEE 100

FHA domain; This entry represents a divergent FHA domain which in PNK binds to phosphorylated segment of XRCC1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724    4 CWLVRQDCWHQRIKLPHLEAVVIGRSPETKITDKKCSRQQVQLKAECNKRYVNVKQMGVNPTSIDEVVIGKDREMKLLPG 83
Cdd:pfam17913   1 CYLVSLEGTHPPIPLPHGQPVVIGRGPETGITDKKCSRNQVELKADCEKRYVKVKQLGANPSGLNGFKLKKGESYELKHG 80

                          90
                  ....*....|....*..
gi 564350724   84 QVLHMVNELYPYMVEFE 100
Cdd:pfam17913  81 DVLELLNGKHPHRVEFN 97

polynucleotide 5'-kinase 3'-phosphatase; This model represents the metazoan 5'-polynucleotide-kinase-3'-phosphatase, PNKP, which is believed to be involved in repair of oxidative DNA damage. Removal of 3' phosphates is essential for the further processing of the break by DNA polymerases. The central phosphatase domain is a member of the IIIA subfamily (TIGR01662) of the haloacid dehalogenase (HAD) superfamily of aspartate-nucleophile hydrolases. As is common in this superfamily, the enzyme is magnesium dependent. A difference between this enzyme and other HAD-superfamily phosphatases is in the third conserved catalytic motif which usually contains two conserved aspartate residues believed to be involved in binding the magnesium ion. Here, the second aspartate is replaced by a conserved arginine residue which may indicate an interaction with the phosphate backbone of the substrate. Very close relatives of this domain are also found separate from the N- and C-terminal domains seen here, as in the 3'-phosphatase found in plants. The larger family of these domains is described by TIGR01664. Outside of the phosphatase domain is a P-loop ATP-binding motif associated with the kinase activity. The entry for the mouse homolog appears to be missing a large piece of sequence corresponding to the first conserved catalytic motif of the phosphatase domain as well as the conserved threonine of the second motif. Either this is a sequencing artifact or this may represent a pseudo- or non-functional gene. Note that the EC number for the kinase function is: 2.7.1.78

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724   22 EAVVIGRSPETKITDKKCSRQQVQLKAECNKRYVNVKQMGVNPTSIDEVVIGKDREMKLLPGQVLHMVNELYPYMVEFEE 101
Cdd:TIGR01663  32 GALFLGRGPETGIRDRKCSKRQIELQADLEKATVALKQLGVNPCGTGGLELKPGGEGELGHGDLLEIVNGLHPLTLQFEE 111

                          90
                  ....*....|....*
gi 564350724  102 VAESPNVTQRKRKRP 116
Cdd:TIGR01663 112 TFNPEPEPDKEKAEP 126

Purine nucleoside phosphoramidase/Ap4A hydrolase, histidine triade (HIT) family [Nucleotide transport and metabolism, General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724 169 VYKDDQVVVIKDKYPKARHHWLVLP---WASISSLKVvtsehlELLKHMHAVGEKVIADF-TGSSKLRFRLGYHAIP--- 241
Cdd:COG0537   18 VYEDEHVLAFLDINPYAPGHTLVIPkrhVASLFDLTP------EELAELMRLAQKVAKALrKALGPDGFNLGINNGEaag 91

                         90
                 ....*....|.
gi 564350724 242 -SMSHVHLHVI 251
Cdd:COG0537   92 qTVPHLHVHVI 102

forkhead associated (FHA) domain found in aprataxin and similar proteins; Aprataxin (EC 3.6.1.71/EC 3.6.1.72), also called forkhead-associated domain histidine triad-like protein (FHA-HIT), is a DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair, and base excision repair. It catalyzes the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined. It can also hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity. Likewise, it catalyzes the release of 3'-linked guanosine (DNAppG) and inosine (DNAppI) from DNA but has higher specific activity with 5'-linked adenosine (AppDNA). Mutations in the gene APTX have been associated with ataxia-ocular apraxia. Aprataxin contains an FHA domain at its N-terminus. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724   2 RVCWLVRQDCWHQRIKLPHLEAVVIGRSPETKITDKKCSRQQVQLKAECNKRYVNVKQMGVNPTSIDEVVIGKDREMKLL 81
Cdd:cd22735    1 RVCWLVSKDGRHLRIRLPHLEAVVIGRGPETKITDKKCSRHQVQLKADCNKGYVKVKQLGVNPTSIDLVDIGKDEEVKLK 80

                         90       100
                 ....*....|....*....|
gi 564350724  82 PGQVLHMVNELYPYMVEFEE 101
Cdd:cd22735   81 PGQVLHIVNQLYPYIVEFEE 100

FHA domain; This entry represents a divergent FHA domain which in PNK binds to phosphorylated segment of XRCC1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724    4 CWLVRQDCWHQRIKLPHLEAVVIGRSPETKITDKKCSRQQVQLKAECNKRYVNVKQMGVNPTSIDEVVIGKDREMKLLPG 83
Cdd:pfam17913   1 CYLVSLEGTHPPIPLPHGQPVVIGRGPETGITDKKCSRNQVELKADCEKRYVKVKQLGANPSGLNGFKLKKGESYELKHG 80

                          90
                  ....*....|....*..
gi 564350724   84 QVLHMVNELYPYMVEFE 100
Cdd:pfam17913  81 DVLELLNGKHPHRVEFN 97

Scavenger mRNA decapping enzyme C-term binding; This family consists of several scavenger mRNA decapping enzymes (DcpS) and is the C-terminal region. DcpS is a scavenger pyrophosphatase that hydrolyses the residual cap structure following 3' to 5' decay of an mRNA. The association of DcpS with 3' to 5' exonuclease exosome components suggests that these two activities are linked and there is a coupled exonucleolytic decay-dependent decapping pathway. The C-terminal domain contains a histidine triad (HIT) sequence with three histidines separated by hydrophobic residues. The central histidine within the DcpS HIT motif is critical for decapping activity and defines the HIT motif as a new mRNA decapping domain, making DcpS the first member of the HIT family of proteins with a defined biological function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724  160 ISMKDPKMQVYKDDQVVVIKDKYPKARHHWLVLPWASISSLKVVTSEHLELLKHMHAVGEKVIAD-FTGSSKLRFRLGYH 238
Cdd:pfam11969   8 AKGEEPERVVYEDEGFVVFKDIKPKAPLHLLVIPKRHIKSLRDLTPEHLPLLEHMREVAKKVIEEkYIGVDRDELRLGFH 87

                          90       100
                  ....*....|....*....|....*..
gi 564350724  239 AIPSMSHVHLHVISQDFDSPCLKNKKH 265
Cdd:pfam11969  88 YPPSVYHLHLHVISPDFESLGLGRKKG 114

forkhead associated (FHA) domain found in aprataxin, bifunctional polynucleotide phosphatase/kinase (PNKP), aprataxin and PNK-like factor (APLF), and similar proteins; The family includes aprataxin, PNKP, and APLF. Aprataxin (EC 3.6.1.71/EC 3.6.1.72), also called forkhead-associated domain histidine triad-like protein (FHA-HIT), is a DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair, and base excision repair. It catalyzes the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined. It can also hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity. Likewise, it catalyzes the release of 3'-linked guanosine (DNAppG) and inosine (DNAppI) from DNA but has higher specific activity with 5'-linked adenosine (AppDNA). PNKP (EC 3.1.3.32/EC 2.7.1.78), also called DNA 5'-kinase/3'-phosphatase, or polynucleotide kinase-3'-phosphatase, plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways. Through its two catalytic activities, PNKP ensures that DNA termini are compatible with extension and ligation by either removing 3'-phosphates from, or by phosphorylating 5'-hydroxyl groups on, the ribose sugar of the DNA backbone. APLF, also called apurinic-apyrimidinic endonuclease APLF, PNK and APTX-like FHA domain-containing protein, or XRCC1-interacting protein 1 (XIP1), is a novel apurinic-apyrimidinic (AP) endonuclease and 3'-5' exonuclease with conserved zinc-finger-like motifs involved in single-strand and double-strand DNA break repair. It is recruited to sites of DNA damage through interaction with poly(ADP-ribose), a polymeric post-translational modification synthesized transiently at sites of chromosomal damage to accelerate DNA strand break repair reactions. It can introduce nicks at hydroxyuracil and other types of pyrimidine base damage. Together with PARP3, APLF promotes the retention of the LIG4-XRCC4 complex on chromatin and accelerate DNA ligation during non-homologous end-joining (NHEJ). Members of this family contain an FHA domain at their N-terminus. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724  10 DCWHQRIKLPHLEAVVIGRSPETKITDKKCSRQQVQLKAECNKRYVNVKQMGVNPTSID-----EVVIGKDREMKLLPGQ 84
Cdd:cd22671    7 GGGGPPIELKEGGPTVLGRGPLLGIRDKRVSRKQAEITVDDDTGSVTVTQLGTNPSFVNradgeGKVLKKGESVELKDGD 86

                         90
                 ....*....|....*
gi 564350724  85 VLHMVNELYPYMVEF 99
Cdd:cd22671   87 VISLLPGKYPFRVEI 101

C2HE / C2H2 / C2HC zinc-binding finger; zf-C2HE is an unusual zinc-binding domain found in fungi, plants and metazoa. It is often found at the C-terminus of HIT-domain-containing proteins, pfam01230. In fungi the fourth ligand is a Glu, in plants it is Cys and in metazoans it is usually a His. The fourth ligand is often mutated in neurogenerative disease-states.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 564350724  270 NTEYFLESQAVIKMVQEAGRVTVKDGTCELLKLPLRCHECQQLLPSIPQLKEHLRKHW 327
Cdd:pfam16278   1 NTPFFVPLDDVPEWLEEDGKIELLPSEVLLLKTPLKCHRCGNFGNNFPKLKAHLEEHF 58

Purine nucleoside phosphoramidase/Ap4A hydrolase, histidine triade (HIT) family [Nucleotide transport and metabolism, General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724 169 VYKDDQVVVIKDKYPKARHHWLVLP---WASISSLKVvtsehlELLKHMHAVGEKVIADF-TGSSKLRFRLGYHAIP--- 241
Cdd:COG0537   18 VYEDEHVLAFLDINPYAPGHTLVIPkrhVASLFDLTP------EELAELMRLAQKVAKALrKALGPDGFNLGINNGEaag 91

                         90
                 ....*....|.
gi 564350724 242 -SMSHVHLHVI 251
Cdd:COG0537   92 qTVPHLHVHVI 102

forkhead associated (FHA) domain found in aprataxin and PNK-like factor (APLF) and similar proteins; APLF, also called apurinic-apyrimidinic endonuclease APLF, PNK and APTX-like FHA domain-containing protein, or XRCC1-interacting protein 1 (XIP1), is a novel apurinic-apyrimidinic (AP) endonuclease and 3'-5' exonuclease with conserved zinc-finger-like motifs involved in single-strand and double-strand DNA break repair. It is recruited to sites of DNA damage through interaction with poly(ADP-ribose), a polymeric post-translational modification synthesized transiently at sites of chromosomal damage to accelerate DNA strand break repair reactions. It can introduce nicks at hydroxyuracil and other types of pyrimidine base damage. Together with PARP3, APLF promotes the retention of the LIG4-XRCC4 complex on chromatin and accelerate DNA ligation during non-homologous end-joining (NHEJ). APLF contains an FHA domain at its N-terminus. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564350724  14 QRIKLPhLEAVVIGRSPETKITDKKCSRQQVQLKAECNKryVNVKQMGVNP-----TSIDE-VVIGKDREMKLLPGQVLH 87
Cdd:cd22717   11 KRIELP-PGETTIGRGPFLGITDKRVSRNHAILEVVDGK--LRIKPTHTNPcfyqpSGKSKlIPLKKDEWQELENGDSFS 87

                         90
                 ....*....|
gi 564350724  88 MVNELYPYMV 97
Cdd:cd22717   88 LLPDKLIFRV 97