Structure-function relationship of FGF2 oligomers forming dynamic membrane pores in unconventional protein secretion

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Fibroblast Growth Factor 2 (FGF2) is a secretory protein that is transported into the extracellular space by unconventional means. The core process of this unusual secretory pathway is triggered by PI(4,5)P2-dependent oligomerization of FGF2 at the inner plasma membrane leaflet. This, in turn, initiates a highly dynamic membrane remodeling event that results in the formation of a lipidic membrane pore with a toroidal architecture. Membrane-inserted FGF2 oligomers are accommodated in the central hydrophilic space of these membrane pores. They represent transient translocation intermediates that are captured and disassembled at the outer plasma membrane leaflet, a process mediated by the cell surface heparan sulfate proteoglycan Glypican-1 (GPC-1). Thus, FGF2 translocation across the plasma membrane involves four types of membrane remodeling in a sequential manner with (i) transversal reorganization [PI(4,5)P2-dependent FGF2 membrane recruitment at the inner leaflet], (ii) lateral segregation [PI(4,5)P2 partitioning into cholesterol-enriched nanodomains], (iii) morphological transformation (membrane curvature as part of a toroidal pore) and (iv) topological transformation (removing toroidal membrane pores when FGF2 translocation is completed restoring the regular bilayer structure). In this project, we will combine experimental work with molecular dynamics simulations to reveal the molecular mechanism that enables FGF2 to dynamically remodel the plasma membrane through PI(4,5)P2-dependent oligomerization, generating a translocation intermediate through which it can reach the extracellular space. A deep understanding of this process is fundamental for developing inhibitors that block unconventional secretion of FGF2 from tumor cells and their cellular microenvironment. Developed further into drugs for cancer therapy, such inhibitors have great potential for treating chemoresistances that FGF2 exerts, for example, in acute myeloid leukemia.