STRUCTURE OF THE HIGH-AFFINITY COMPLEX OF INOSITOL TRISPHOSPHATE WITH A PHOSPHOLIPASE-C PLECKSTRIN HOMOLOGY DOMAIN

The X-ray crystal structure of the high affinity complex between the pleckstrin homology (PH) domain from rat phospholipase C-delta(1) (PLC-delta(1)) and inositol-(1,4,5)-trisphosphate (Ins(1,4,5)P-3) has been refined to 1.9 Angstrom resolution. The domain fold is similar to others of known structure. Ins(1,4,5)P-3 binds on the positively charged face of the electrostatically polarized domain, interacting predominantly with the beta 1/beta 2 and beta 3/beta 4 loops. The 4- and B-phosphate groups of Ins(1,4,5)P-3 interact much more extensively than the l-phosphate. Two amino acids in the PLC-delta(1) PH domain that contact lns(1,4,5)P-3 have counterparts in the Bruton's tyrosine kinase (Btk) PH domain, where mutational changes cause inherited agammaglobulinemia, suggesting a mechanism for loss of function in Btk mutants. Using electrostatics and varying levels of head-group specificity, PH domains may localize and orient signaling proteins, providing a general membrane targeting and regulatory function.