InterPro domain: IPR036265

The histidine triad motif (HIT) consists of the conserved sequence HXHXHXX (where X is a hydrophobic amino acid) at the enzymatic catalytic centre, in which the second histidine is strictly conserved and participates in catalysis with the third histidine [ 1 , 2 , 3 ]. Proteins containing HIT domains form a superfamily of nucleotide hydrolases and transferases that act on the alpha-phosphate of ribonucleotides [ 4 , 4 ]. They are highly conserved from archaea to humans and are involved in galactose metabolism, DNA repair, and tumor suppression [ 4 ]. HIT-containing proteins can be divided in five families based on catalytic specificities, sequence compositions, and structural similarities of its members:

• Hint family of protein kinase-interacting proteins, the most ancient class in this superfamily. These include adenosine 5'-monophosphoramide hydrolases (e.g. HIT-nucleotide-binding protein, or HINT) [ 5 , 6 ]. They also have a conserved zinc-binding motif C-X-X-C (where C is a cysteine residue and X is a hydrophobic residue), and a zinc ion is coordinated by these cysteine residues, together with the first histidine residue [ 6 ].
• Fragile HIT protein, or FINT, whose name is due to its high rate of mutation at its locus on chromosome 3 in many cancers has been characterised as a tumor suppressor and plays a role in the hydrolysis of dinucleotide polyphosphates [ 6 , 6 ]. HINT and FINT HIT domains have a topology similar to that found in the N-terminal of protein kinases [ 6 ].
• GalT family. These include specific nucleoside monophosphate transferases (e.g. galactose-1-phosphate uridylyltransferase, diadenosine tetraphosphate phosphorylase, and adenylyl sulphate:phosphate adenylytransferase). These HIT domains are a duplication consisting of 2 HIT-like motifs. This family binds zinc and iron [ 7 , 7 ].
• Aprataxin, which hydrolyses both dinucleotide polyphosphates and phophoramidates, and is involved in DNA repair systems [ 8 , 8 ].
• mRNA decapping enzyme family. These include enzymes such as DcpS and Dcp2. The HIT-domain is usually C-terminal in these proteins [ 8 , 9 ].

This superfamily also includes CDP-diacylglycerol pyrophosphatases, CDH, which play a role in phospholipid metabolism and regulates phosphatidylinositol levels [ 10 ], the C-terminal CwfJ domains of CWF19-like protein DRN1 from Saccharomyces cerevisiae ( P53255 ) which is involved branched RNA metabolism, modulating the turnover of lariat-intron pre-mRNAs by the lariat-debranching enzyme DBR1 and its homologues. This C-terminal Cwfj domains contain evolutionarily conserved cysteine and histidine residues in an arrangement similar to the CCCH-class of zinc fingers [ 11 , 12 ].

1. [Histidine triad protein superfamily--biological function and enzymatic activity]. Postepy Biochem 58, 302-13
2. Structural characterization of human histidine triad nucleotide-binding protein 2, a member of the histidine triad superfamily. FEBS J 280, 3389-98
3. Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Biochemistry 41, 9003-14
4. Crystal Structure of Histidine Triad Nucleotide-Binding Protein from the Pathogenic Fungus Candida albicans. Mol Cells 42, 56-66
5. Histidine triad nucleotide-binding protein 1 up-regulates cellular levels of p27KIP1 by targeting ScfSKP2 ubiquitin ligase and Src. J Biol Chem 284, 5265-76
6. HinT proteins and their putative interaction partners in Mollicutes and Chlamydiaceae. BMC Microbiol. 5, 27
7. Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase. Hum Mol Genet 25, 2234-2244
8. Functional analysis of mRNA scavenger decapping enzymes. RNA 10, 1412-22
9. Molecular basis of the selective processing of short mRNA substrates by the DcpS mRNA decapping enzyme. Proc Natl Acad Sci U S A 117, 19237-19244
10. Polycyclic aromatic hydrocarbons in human bronchial carcinoma. Cancer Lett 1, 189-95
11. A homolog of lariat-debranching enzyme modulates turnover of branched RNA. RNA 20, 1337-48
12. Proteomics analysis reveals stable multiprotein complexes in both fission and budding yeasts containing Myb-related Cdc5p/Cef1p, novel pre-mRNA splicing factors, and snRNAs. Mol. Cell. Biol. 22, 2011-24