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 672052225   1 MGVNPTSIDEVVIGKDREMKLLPGQVLHMVNELYPYMVEFEE 42
Cdd:cd22735   59 LGVNPTSIDLVDIGKDEEVKLKPGQVLHIVNQLYPYIVEFEE 100

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 672052225  101 ISMKDPKMQVYKDDQVVVIKDKYPKARHHWLVLPWASISSLKVVTSEHLELLKHMHAVGEKVIAD-FTGSSKLRFRLGYH 179
Cdd:pfam11969   8 AKGEEPERVVYEDEGFVVFKDIKPKAPLHLLVIPKRHIKSLRDLTPEHLPLLEHMREVAKKVIEEkYIGVDRDELRLGFH 87

                          90       100
                  ....*....|....*....|....*..
gi 672052225  180 AIPSMSHVHLHVISQDFDSPCLKNKKH 206
Cdd:pfam11969  88 YPPSVYHLHLHVISPDFESLGLGRKKG 114

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 672052225  211 NTEYFLESQAVIKMVQEAGRVTVKDGTCELLKLPLRCHECQQLLPSIPQLKEHLRKHW 268
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 672052225 110 VYKDDQVVVIKDKYPKARHHWLVLP---WASISSLKVvtsehlELLKHMHAVGEKVIADF-TGSSKLRFRLGYHAIP--- 182
Cdd:COG0537   18 VYEDEHVLAFLDINPYAPGHTLVIPkrhVASLFDLTP------EELAELMRLAQKVAKALrKALGPDGFNLGINNGEaag 91

                         90
                 ....*....|.
gi 672052225 183 -SMSHVHLHVI 192
Cdd:COG0537   92 qTVPHLHVHVI 102

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 672052225  101 ISMKDPKMQVYKDDQVVVIKDKYPKARHHWLVLPWASISSLKVVTSEHLELLKHMHAVGEKVIAD-FTGSSKLRFRLGYH 179
Cdd:pfam11969   8 AKGEEPERVVYEDEGFVVFKDIKPKAPLHLLVIPKRHIKSLRDLTPEHLPLLEHMREVAKKVIEEkYIGVDRDELRLGFH 87

                          90       100
                  ....*....|....*....|....*..
gi 672052225  180 AIPSMSHVHLHVISQDFDSPCLKNKKH 206
Cdd:pfam11969  88 YPPSVYHLHLHVISPDFESLGLGRKKG 114

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 672052225  211 NTEYFLESQAVIKMVQEAGRVTVKDGTCELLKLPLRCHECQQLLPSIPQLKEHLRKHW 268
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 672052225   1 MGVNPTSIDEVVIGKDREMKLLPGQVLHMVNELYPYMVEFEE 42
Cdd:cd22716   56 LGPNPSSVGGKLLEKGDEAELSPGETLHLLNGKYPHTVYFEG 97

forkhead associated (FHA) domain found in bifunctional polynucleotide phosphatase/kinase (PNKP) and similar proteins; 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. PNKP contains an FHA domain at its N-terminus. The FHA domain is a small phosphopeptide recognition module.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 672052225   1 MGVNPTSIDEVVIGKDREMKLLPGQVLHMVNELYPYMVEFEE 42
Cdd:cd22736   58 LGVNPSSVGEQELKPGLSGSLKEGQTLYLVNGLYPLTLRFEE 99

HIT family: HIT (Histidine triad) proteins, named for a motif related to the sequence HxHxH/Qxx (x, a hydrophobic amino acid), are a superfamily of nucleotide hydrolases and transferases, which act on the alpha-phosphate of ribonucleotides. On the basis of sequence, substrate specificity, structure, evolution and mechanism, HIT proteins are classified in the literacture into three major branches: the Hint branch, which consists of adenosine 5' -monophosphoramide hydrolases, the Fhit branch, that consists of diadenosine polyphosphate hydrolases, and the GalT branch consisting of specific nucloside monophosphate transferases. Further sequence analysis reveals several new closely related, yet uncharacterized subgroups.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 672052225 110 VYKDDQVVVIKDKYPKARHHWLVLPWASISSL----KVVTSEHLELLKHMHAVGEKviaDFTGSSkLRFRLGYHAIP--S 183
Cdd:cd00468    1 VPDDEHSFAFVNLKPAAPGHVLVCPKRHVETLpdldEALLADLVITAQRVAAELEK---HGNVPS-LTVFVNDGAAAgqS 76

                 ....*....
gi 672052225 184 MSHVHLHVI 192
Cdd:cd00468   77 VPHVHLHVL 85