Pi(4,5)P2 Lipid Binding Induces a Reorientation of FGF2 Molecules Near Membrane Surface to Facilitate the Unconventional Oligomerization-Dependent Secretion Process as Revealed by a Combined FTIR/NMR/X-Ray Study

Abstract

Fibroblast growth factor 2 (FGF2) secreted by an unconventional mechanism has been suggested through a membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent process by involving FGF2 oligomerization and lipidic membrane pore formation (Steringer et l., J. Biol. Chem, 2012, 287, 27659), but the mechanism of lipid-induced oligomerization remains elusive. Herein, we demonstrate by a combined lipid monolayer/FTIR method that PI(4,5)P2 binding to FGF2 induce a reorientation of FGF2 molecule near membrane surface to allow the exposure of hydrophobic surface responsible for FGF2 dimer formation. By using the structural information of FGF2/ PI(4,5)P2 complex obtained by NMR and FGF2 dimeric contact surface obtained by X-ray, we further illustrate a molecular mechanism responsible for lipid-induced FGF2 oligomerization process. The results not only provide a structural basis for FGF2 oligomerization near membrane surface, but also suggest a novel PI(4,5)P2 - induced protruding, rather than insertion, process as a crucial event to trigger the proper orientation of FGF2 molecule for its oligomerizations.