HIT (histidine triad) proteins, named for a short motif related to the sequence (His-x-His-x-His-x-x, where x is a hydrophobic residue) [1,2] are a superfamily of nucleotide hydrolases which acts on the α-phosphate of ribonucleotides [3,4]. This superfamily can be divided in two branches: the Hint branch that is the most widely conserved and has representatives in all cellular life and the Fhit (for “fragile histidine triad”) branch which is only found in animals and fungi. The two branches share a conserved core region of about 1oo amino acids, the HIT domain.

Crystal structures of the HINT-nucleotide complexe revealed that the HIT domain is related to GalT nucleotide-binding proteins (see <PDOC00108>) (see <PDB:3RHN>) [3]. The GalT monomer can be seen as consisting of two repeated HIT domains. Their nucleotide binding sites also retain some of the same residues for binding a nucleoside monophosphate. The histidine triad is located outside the nucleotide binding pocket and stabilize it.

Some proteins known to contain a HIT domain are listed below:

• Mammalian protein HINT (also known as protein kinase C inhibitor 1 or PKCI- 1). HINT was incorrectly thought to be a specific inhibitor of PKC. It has been shown to bind zinc.
• Fission yeast diadenosine 5',5'''-P1,P4-tetraphosphate asymmetrical hydrolase (Ap4Aase) (EC 3.6.1.17) (gene aph1), which cleaves A-5'-PPPP-5'A to yield AMP and ATP.
• FHIT, a human protein whose gene is altered in different tumors and which acts as a diadenosine 5',5'''-P1,P3-triphosphate hydrolase (Ap3Aase) (EC 3.6.1.29) cleaving A-5'-PPP-5'A to yield AMP and ADP.
• Yeast proteins HNT1 and HNT2.
• Maize zinc-binding protein ZBP14.
• Escherichia coli hypothetical protein ycfF and a related protein in all sequenced bacterial genomes and some archaeal genomes.
• Caenorhabditis elegans hypothetical protein F21C3.3.

As a signature pattern, we selected the region of the histidine triad. We also developed a profile that covers the whole HIT domain.