The MACPF/CDC family of pore-forming toxins

Abstract

Pore-forming toxins (PFTs) are commonly associated with bacterial pathogenesis. In eukaryotes, however, PFTs operate in the immune system or are deployed for attacking prey (e.g. venoms). This review focuses upon two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF). CDCs are produced by Gram-positive bacteria and lyse or permeabilize host cells or intracellular organelles during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles and function in immunity, invasion and development. The structure and molecular mechanism of several CDCs are relatively well characterized. Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane beta-barrel. In contrast, the structure and mechanism of MACPF proteins has remained obscure. Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold. Together with biochemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development.

Fig. 1

A. The structure of perfringolysin O [PDB identifier: 1PFO (Rossjohn et al., 1997)]. The central β-sheet that contains a 90° bend is in blue. The two transmembrane regions TMH1 and TMH2 are in red and are labelled. The C-terminal Ig domain is in pale green. B. Schematic showing the molecular mechanism of CDC membrane insertion. The two clusters of α-helices (red cylinders) unwind and insert into the membrane as β-sheets. C. X-ray crystal structure of Plu-MACPF [PDB identifier 2QP2 (Rosado et al., 2007)]. Colouring is as for Fig. 1A, with the central β-sheet in blue and the two clusters of α-helices corresponding to TMH1 and TMH2 labelled. The location of the binding site for CD59 on C8α and C9 is at the TMH2 region.

Fig. 2

Model of the pore form of a MACPF proteins in a lipid bilayer (using the Plu-MACPF structure as a template, PDB ID: 2QP2).