Molecular insights into conformational dynamics associated with the open-closed-phosphorylated states of PITPα

Abstract

AbstractPhosphatidylinositol transfer proteins (PITPα) are lipid carrier proteins that are involved in replenishing the phosphatidylinositol lipid molecules on the plasma membranes. Transitions between the open and closed state conformations are necessary steps in the mechanism of lipid transfer by PITPα. The apo (open state) conformation is assumed to occur at the membrane surface during the lipid exchange while the lipid bound (closed state) conformation is required for transfer activity. The transfer of phosphatidylinositol by PITPα is controlled by the phosphorylation of S166 in its regulatory region. We wanted to decipher the molecular basis for structure-function relationship between the open-closed-phosphorylated states of PITPα. We used all-atom Molecular Dynamics Simulations to study the conformational dynamics in each of these states. Our study shows that the open state is highly dynamic and its transition to closed state would stabilize PITPα. We observed restricted conformational sampling of the phosphorylated state which provide basis for its decreased lipid transfer activity. Further, using analysis of residue-residue contact maps and hydrogen bond interactions we discuss the impact of phosphorylation on the global conformation of PITPα. Overall, our work provides insights into the structural dynamics in each state and their functional significance.