Discovery of molecular and catalytic diversity among human diphosphoinositol-polyphosphate phosphohydrolases - An expanding Nudt family

The turnover of the "high energy" diphosphoinositol polyphosphates by Ca2+- and cyclic nucleotide-modulated enzymes is considered a regulatory, molecu lar switching activity. Target processes may include intracellular traffick ing. Following our earlier identification of a prototype human (d) under ba r iphospho (i) under bar nositol-(p) under bar olyphosphate phosphohydrolas e (hDIPP1), we now describe new 21-kDa human isoforms, hDIPP2 alpha and hDI PP2 beta, distinguished from each other solely by hDIPP2 beta possessing on e additional amino acid (Gln(86)). Candidate DIPP2 alpha and DIPP2 beta hom ologues in rat and mouse were also identified. The rank order for catalytic activity is hDIPP1 > hDIPP2 alpha > hDIPP2 beta. Differential expression o f hDIPP isoforms may provide flexibility in response times of the molecular switches. The 76% identity between hDIPP1 and the hDIPP2s includes conserv ation of an emerging signature sequence, namely, a Nudt (MutT) motif with a GX(2)GX(6)G carboxy extension. Northern and Western analyses indicate expr ession of hDIPP2s is broad but atypically controlled; these proteins are tr anslated from multiple mRNAs that differ in the length of the 3'-untranslat ed region because of utilization of an array of alternative (canonical and noncanonical) polyadenylation signals. Thus, cells can recruit sophisticate d molecular processes to regulate diphosphoinositol polyphosphate turnover.