Here, we propose the transbilayer asymmetry of membrane lipids in general and PI(4,5)P 2 , in particular, to play a critical role in lowering the free energy costs of the conversion of a stable lipid bilayer into a lipidic membrane pore with a toroidal architecture. Furthermore, regarding lateral partitioning, PI(4,5)P 2 is known to be enriched in ordered nanodomains of plasma membranes . Along with recent findings demonstrating that (i) cholesterol tunes FGF2 binding to PI(4,5)P 2 ), (ii) the Na,K-ATPase has multiple contacts to cholesterol regulating its function ) and (iii) the predominant heparan sulfate proteoglycan driving unconventional secretion of FGF2, Glypican-1 (GPC1), is localized in cholesterol-rich domains based upon a GPI anchor , we propose ordered nanodomains with an asymmetric transbilayer distribution of PI(4,5)P 2 to be the organizational principle of the molecular machinery of FGF2 membrane translocation, contributing to fast FGF2 membrane translocation kinetics of about 200 ms as observed in living cells .