Phospholipid-binding domains are key components of signaling pathways that normally drive membrane recruitment of their host protein in vivo. The most numerous Pleckstrin Homology (PH) domains are commonly associated with high affinity, phosphoinositide (PPIns)-specific binding in vitro and membrane-specific targeting in vivo. In fact, the majority of PH domains bind PPIns promiscuously and with low affinity in vitro and are diffusely localized in vivo. A novel class of PH domains - belonging to the OSBP/FAPP family - is identified here with distinct phospholipid-binding properties, having both promiscuous and high affinity for PPIns in vitro. Additionally, the crystal structure of a member of this class - Osh1p PH - has been determined at high resolution. The PPIns-binding properties of another unusual PH domain, belonging to SH3BP2, is also discussed, which has implications in the spatial and temporal regulation of 3-phosphoinositides. Finally, an alkylphospholipid drug is identified that interacts directly with the PH domain of Akt1/PKBalpha in vitro, which has implications in the use of PH domains as possible targets for therapeutic drug intervention.

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