STRUCTURE OF TYPE II-BETA PHOSPHATIDYLINOSITOL PHOSPHATE KINASE - A PROTEIN-KINASE FOLD FLATTENED FOR INTERFACIAL PHOSPHORYLATION

Phosphoinositide kinases play central roles in signal transduction by phosphorylating the inositol ring at specific positions. The structure of one such enzyme, type I1 beta phosphatidylinositol phosphate kinas e, reveals a protein kinase ATP-binding core and demonstrates that all phosphoinositide kinases belong to one superfamily. The enzyme is a d isc-shaped homodimer with a 33 x 48 Angstrom basic flat face that sugg ests an electrostatic mechanism for plasma membrane targeting. Conserv ed basic residues form a putative phosphatidylinositol phosphate speci ficity site. The substrate-binding site is open on one side, consisten t with dual specificity for phosphatidylinositol 3- and 5-phosphates. A modeled complex with membrane-bound substrate and ATP shows how a ph osphoinositide kinase can phosphorylate its substrate in situ at the m embrane interface.