Abstract - Lolicato

FGF2 is a cell survival factor involved in tumour-associated angiogenesis and is secreted via an unconventional pathway involving direct protein translocation across the plasma membrane. Similar to other pore-forming proteins, FGF2 binds to the membrane through a specific protein-lipid interaction, with PI(4,5)P2 acting as trigger for FGF2 disulfide-bridges dimerization, and subsequent high oligomer formation. Our atomic force microscopy data show the formation of ring-like structures as a consequence of this molecular process. Using multiscale molecular dynamics simulations, we examined the surrounding lipids and found that the FGF2 oligomer selectively associates with lipids that have a high negative  charge and intrinsic curvature, with over 60% of the surrounding lipids being non-bilayer lipids. This interaction is likely to induce a local lipid phase transition and a charge gradient, resulting in membrane destabilization. This destabilization will lead to the opening of a membrane pore, releasing tension and facilitating protein translocation. We propose that the geometry of FGF2 aggregates and their lipid sorting capacity are crucial for protein translocation, suggesting a shared mechanism with other pore-forming proteins that assemble into ring-like structures.

Alessandra Griffo (Saarland University), Daniel Bayer (Heidelberg University Biochemistry Center), Walter Nickel (Heidelberg University Biochemistry Center) and Fabio Lolicato (Heidelberg University Biochemistry Center)