Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 or PIP2) has emerged as a key regulator of signal transduction in cell membranes. Hydrolysis of PI(4,5)P2 by phospholipase C generates two important second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). Phosphorylation of PI(4,5)P2 by PI-3 kinase generates another second messenger, PI(3,4,5)P3. In addition, PI(4,5)P3 itself plays a crucial role in many different cellular processes including membrane trafficking and transport, exocytosis and endocytosis, and cytoskeletal attachment.

We are interested in how the concentration of PIP2 is regulated in cell membranes so that it can carry out its many functions in a coordinated fashion. One mechanism of regulation is by MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate protein), a membrane-associated protein that participates in many cell signaling pathways. MARCKS is able to sequester PIP2 in lateral membrane domains when its highly positively charged effector domain (151-175) is not phosphorylated. Phosphorylation by PKC releases the effector domain from the membrane surface , which in turn frees locally sequestered PIP2. We are in the process of determining the structure of the membrane bound effector domain of MARCKS and how it interacts with PI(4,5)P2.