Abstract
Phosphatidylinositol transfer protein (PITP) is essential for phospholipase C signaling and for constitutive and regulated vesicular traffic. PITP has a single lipid-binding site that can reversibly bind phosphatidylinositol (PI) and phosphatidylcholine (PC) and transfer these lipids between membrane compartments in vitro. The role of the carboxyl terminus was examined by comparing wild-type PITPalpha with PITPalpha in which 5, 10, and 20 amino acids were deleted from the C terminus. Delta5- and Delta10-PITP had reduced PI and PC transfer activities compared with wild-type PITP, with the effect on PI transfer being more marked than that on PC transfer. Delta20-PITP was inactive at all concentrations tested. All three truncated mutants were unable to restore G-protein-mediated phospholipase Cbeta stimulation in HL-60 cells. Delta5- and Delta10-PITP, but not Delta20-PITP, inhibited the signaling function of wild-type protein without any effect on lipid transfer in vitro. We conclude that (a) the carboxyl terminus of PITP plays a critical role in phospholipase C signaling; (b) the transfer activity is not the only determining factor that dictates the restorative function of PITP in inositol lipid signaling; and (c) the dominant inhibitory effects of Delta5- and Delta10-PITP on wild-type PITP in phospholipase C signaling suggest the existence of a receptor for PITP.
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