The histidine triad superfamily of nucleotide-binding proteins

Histidine triad (HIT) proteins were until recently a superfamily of protein s that shared only sequence motifs. Crystal structures of nucleotide-bound forms of histidine triad nucleotide-binding protein (Hint) demonstrated tha t the conserved residues in HIT proteins are responsible for their distinct ive, dimeric, 10-stranded half-barrel structures that form two identical pu rine nucleotide-binding sires. Hint-related proteins, found in all forms of life, and fragile histidine triad (Fhit)-related proteins, found in animal s and fungi, represent the two main branches of the HIT superfamily. Hint h omologs are intracellular receptors for purine mononucleotides whose cellul ar function remains elusive. Fhit homologs bind and cleave diadenosine poly phosphates (Ap(n)A) such as ApppA and AppppA. Fhit-Ap(n)A complexes appear to function in a proapoptotic tumor suppression pathway in epithelial tissu es. In invertebrates, Fhit homologs are encoded as fusion proteins with pro teins related to plant and bacterial nitrilases that are candidate signalin g partners in tumor suppression. (C) 1999 Wiley-Liss, Inc.