Lipid-Protein Partnering during Pore Formation of Fragaceatoxin C

Abstract

Pore-forming toxins (PFT) are proteins that target cell membranes forming water-filled pores across the lipid bilayer. The steps leading to pore formation in PFT begin with membrane partitioning of the water-soluble monomers and are followed by the oligomerization and penetration of the protein subunits through the lipid bilayer. Reshaping of the protein into a final pore is governed by the interplay between the toxin and the physico-chemical landscape of the membrane. For example, in actinoporins (PFT from sea anemones) the presence of sphingomyelin is a strong contributor in making the toxin active. Additionally, when cholesterol is abundant, actinoporins make use of conserved residues to penetrate the membrane. Protein restructuring and lipid redistribution during the formation of the pore often lead to pores with distinct architectures. The pore formed by fragaceatoxin C (FraC), an actinoporin secreted by the sea anemone Actinia fragacea, has been traditionally described to be lined by both protein α-helices and lipid headgroups in a structure resembling a torus (toroidal model). However, recent data point to other alternatives where the protein contribution predominates. Herein, we show our recent findings involving FraC-membrane interaction and how these associate to build a pore mainly composed of protein but where lipids also play an important role.