Specificity determinants in phosphoinositide dephosphorylation: Crystal structure of an archetypal inositol polyphosphate 5-phosphatase

Inositol polyphosphate 5-phosphatases are central to intracellular processe s ranging from membrane trafficking to Ca2+ signaling, and defects in this activity result in the human disease Lowe syndrome. The 1.8 Angstrom resolu tion structure of the inositol polyphosphate 5-phosphatase domain of SPsyna ptojanin bound to Ca2+ and inositol (1,4)-bisphosphate reveals a fold and a n active site His and Asp pair resembling those of several Mg2+-dependent n ucleases. Additional loops mediate specific inositol polyphosphate contacts . The 4-phosphate of inositol (1,4)-bisphosphate is misoriented by 4.6 Angs trom compared to the reactive geometry observed in the apurinic/apyrimidini c endonuclease 1, explaining the dephosphorylation site selectivity of the 5-phosphatases. Based on the structure, a series of mutants are described t hat exhibit altered substrate specificity providing general determinants fo r substrate recognition.