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Structural basis for self-assembly of a cytolytic pore lined by protein and lipid

Koji Tanaka,J. Caaveiro,K. Morante,J. M. González-Mañas,K. Tsumoto

Published 2015 in Nature Communications

ABSTRACT

Pore-forming toxins (PFT) are water-soluble proteins that possess the remarkable ability to self-assemble on the membrane of target cells, where they form pores causing cell damage. Here, we elucidate the mechanism of action of the haemolytic protein fragaceatoxin C (FraC), a α-barrel PFT, by determining the crystal structures of FraC at four different stages of the lytic mechanism, namely the water-soluble state, the monomeric lipid-bound form, an assembly intermediate and the fully assembled transmembrane pore. The structure of the transmembrane pore exhibits a unique architecture composed of both protein and lipids, with some of the lipids lining the pore wall, acting as assembly cofactors. The pore also exhibits lateral fenestrations that expose the hydrophobic core of the membrane to the aqueous environment. The incorporation of lipids from the target membrane within the structure of the pore provides a membrane-specific trigger for the activation of a haemolytic toxin. Actinoporins are water-soluble pore-forming toxins that self-assemble in the membranes of target cells. Here, the authors provide insight into the mechanism of membrane pore formation by solving the structures of several states of the hemolytic protein fragaceatoxin C, including the fully assembled pore.

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