aprataxin related: Aprataxin, a HINT family hydrolase is mutated in ataxia oculomotor apraxia syndrome. All the members of this subgroup have the conserved HxHxHxx (where x is a hydrophobic residue) signature motif. Members of this subgroup are predominantly eukaryotic in origin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568927210  98 LGHWSQGLKMSMKDPKMQVYKDDQVVVIKDKYPKARHHWLVLPWASISSLKVVTSEHLELLKHMHAVGEKVIADFAGSSK 177
Cdd:cd01278    1 LCHFCDIAKRRDPDPEDQVYEDDRVVVFKDIYPKARHHYLVIPKEHIASLKALTKEDVPLLEHMETVGREKLLRSDNTDP 80

                         90       100
                 ....*....|....*....|....
gi 568927210 178 LRFRLGYHAIP--SMSHVHLHVIS 199
Cdd:cd01278   81 SEFRFGFHAPPftSVSHLHLHVIA 104

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
                 ....*....|....*....|....*....|....*....|..
gi 568927210   1 MGVNPTSIDSGVIGKDQEKKLLPGQVLHMVNGLYPYIVEFEE 42
Cdd:cd22735   59 LGVNPTSIDLVDIGKDEEVKLKPGQVLHIVNQLYPYIVEFEE 100

aprataxin related: Aprataxin, a HINT family hydrolase is mutated in ataxia oculomotor apraxia syndrome. All the members of this subgroup have the conserved HxHxHxx (where x is a hydrophobic residue) signature motif. Members of this subgroup are predominantly eukaryotic in origin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568927210  98 LGHWSQGLKMSMKDPKMQVYKDDQVVVIKDKYPKARHHWLVLPWASISSLKVVTSEHLELLKHMHAVGEKVIADFAGSSK 177
Cdd:cd01278    1 LCHFCDIAKRRDPDPEDQVYEDDRVVVFKDIYPKARHHYLVIPKEHIASLKALTKEDVPLLEHMETVGREKLLRSDNTDP 80

                         90       100
                 ....*....|....*....|....
gi 568927210 178 LRFRLGYHAIP--SMSHVHLHVIS 199
Cdd:cd01278   81 SEFRFGFHAPPftSVSHLHLHVIA 104

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 568927210  217 NTEYFLESQAVIKMVQEAGRVTVKDGTCELLKLPLRCHECQQLLPSIPQLKEHLRKHW 274
Cdd:pfam16278   1 NTPFFVPLDDVPEWLEEDGKIELLPSEVLLLKTPLKCHRCGNFGNNFPKLKAHLEEHF 58

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 568927210    2 GVNPTSIDSGVIGKDQEKKLLPGQVLHMVNGLYPYIVEFE 41
Cdd:pfam17913  58 GANPSGLNGFKLKKGESYELKHGDVLELLNGKHPHRVEFN 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 568927210    1 MGVNPTSIDSGVIGKDQEKKLLPGQVLHMVNGLYPYIVEFEEVAESPNltqrkrkrsdcdseEMEAESGTGLAPGSSPSQ 80
Cdd:TIGR01663  70 LGVNPCGTGGLELKPGGEGELGHGDLLEIVNGLHPLTLQFEETFNPEP--------------EPDKEKAEPLSSQDEKRD 135

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568927210   81 CSVSPKKDKNGATKKESLGHW----SQGLKMSmkdPKMQVYKDDQvVVIKDK----YPKARHHWlvlpwasisslKVVTS 152
Cdd:TIGR01663 136 AEKPEKRDRKGNPGWENLEKLliftAAGVKGQ---EKIAGFDLDG-TIIKTKsgkvFPKGPDDW-----------QIIFP 200

                         170
                  ....*....|....*..
gi 568927210  153 EHLELLKHMHAVGEKVI 169
Cdd:TIGR01663 201 EIPEKLKELEADGFKIC 217

aprataxin related: Aprataxin, a HINT family hydrolase is mutated in ataxia oculomotor apraxia syndrome. All the members of this subgroup have the conserved HxHxHxx (where x is a hydrophobic residue) signature motif. Members of this subgroup are predominantly eukaryotic in origin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568927210  98 LGHWSQGLKMSMKDPKMQVYKDDQVVVIKDKYPKARHHWLVLPWASISSLKVVTSEHLELLKHMHAVGEKVIADFAGSSK 177
Cdd:cd01278    1 LCHFCDIAKRRDPDPEDQVYEDDRVVVFKDIYPKARHHYLVIPKEHIASLKALTKEDVPLLEHMETVGREKLLRSDNTDP 80

                         90       100
                 ....*....|....*....|....
gi 568927210 178 LRFRLGYHAIP--SMSHVHLHVIS 199
Cdd:cd01278   81 SEFRFGFHAPPftSVSHLHLHVIA 104

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 568927210  217 NTEYFLESQAVIKMVQEAGRVTVKDGTCELLKLPLRCHECQQLLPSIPQLKEHLRKHW 274
Cdd:pfam16278   1 NTPFFVPLDDVPEWLEEDGKIELLPSEVLLLKTPLKCHRCGNFGNNFPKLKAHLEEHF 58

forkhead associated (FHA) domain found in aprataxin, bifunctional polynucleotide phosphatase/kinase (PNKP), and similar proteins; The subfamily includes aprataxin and PNKP. 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. Both aprataxin and PNKP contain an FHA domain at their N-terminus. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 568927210   1 MGVNPTSIDSGVIGKDQEKKLLPGQVLHMVNGLYPYIVEFEE 42
Cdd:cd22716   56 LGPNPSSVGGKLLEKGDEAELSPGETLHLLNGKYPHTVYFEG 97

HIT domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568927210  116 VYKDDQVVVIKDKYPKARHHWLVLPWASISSLKVVTSEHL-ELLKHMHAVGEKVIADFAGSSklrFRL----GYHAIPSM 190
Cdd:pfam01230   9 VYEDDLVLAFLDIDPQAPGHILVIPKKHIRELHDLTPEELgDLMSVAQKVARALGKVFKADG---YRIvinnGAHAGQSV 85

                          90
                  ....*....|...
gi 568927210  191 SHVHLHVISQDFD 203
Cdd:pfam01230  86 PHLHIHVIPRRKH 98

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 568927210 116 VYKDDQVVVIKDKYPKARHHWLVLP---WASISSLKVvtsehlELLKHMHAVGEKVIADF-AGSSKLRFRLGYHAIP--- 188
Cdd:COG0537   18 VYEDEHVLAFLDINPYAPGHTLVIPkrhVASLFDLTP------EELAELMRLAQKVAKALrKALGPDGFNLGINNGEaag 91

                         90
                 ....*....|.
gi 568927210 189 -SMSHVHLHVI 198
Cdd:COG0537   92 qTVPHLHVHVI 102

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 568927210    1 MGVNPTSIDSGVIGKDQEKKLLPGQVLHMVNGLYPYIVEFEEVAESPNltqrkrkrsdcdseEMEAESGTGLAPGSSPSQ 80
Cdd:TIGR01663  70 LGVNPCGTGGLELKPGGEGELGHGDLLEIVNGLHPLTLQFEETFNPEP--------------EPDKEKAEPLSSQDEKRD 135

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568927210   81 CSVSPKKDKNGATKKESLGHW----SQGLKMSmkdPKMQVYKDDQvVVIKDK----YPKARHHWlvlpwasisslKVVTS 152
Cdd:TIGR01663 136 AEKPEKRDRKGNPGWENLEKLliftAAGVKGQ---EKIAGFDLDG-TIIKTKsgkvFPKGPDDW-----------QIIFP 200

                         170
                  ....*....|....*..
gi 568927210  153 EHLELLKHMHAVGEKVI 169
Cdd:TIGR01663 201 EIPEKLKELEADGFKIC 217