Abstract
In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers. MAC directly lyses pathogens by a ‘multi-hit' mechanism; however, sublytic MAC pores on host cells activate signalling pathways. Previous studies have described the structures of individual MAC components and subcomplexes; however, the molecular details of its assembly and mechanism of action remain unresolved. Here we report the electron cryo-microscopy structure of human MAC at subnanometre resolution. Structural analyses define the stoichiometry of the complete pore and identify a network of interaction interfaces that determine its assembly mechanism. MAC adopts a ‘split-washer' configuration, in contrast to the predicted closed ring observed for perforin and cholesterol-dependent cytolysins. Assembly precursors partially penetrate the lipid bilayer, resulting in an irregular β-barrel pore. Our results demonstrate how differences in symmetric and asymmetric components of the MAC underpin a molecular basis for pore formation and suggest a mechanism of action that extends beyond membrane penetration.
Highlights
In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers
It is essential for defense against Neisseria meningitidis, with genetic deficiencies in MAC components leading to recurrent infections[2]
CDC/MACPF proteins comprise a large family of structurally related molecules, many of which form pores involved in host immunity and bacterial pathogenesis
Summary
In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers. Previous studies have described the structures of individual MAC components and subcomplexes; the molecular details of its assembly and mechanism of action remain unresolved. Our results demonstrate how differences in symmetric and asymmetric components of the MAC underpin a molecular basis for pore formation and suggest a mechanism of action that extends beyond membrane penetration. Activation of complement triggers assembly of the membrane attack complex (MAC), a multiprotein pore that inserts into and directly lyses microbes[1]. The association of cholesterol-dependent cytolysin/MAC/ perforin-like (CDC/MACPF) domains, found in all but C5b, is responsible for pore formation. CDC/MACPF proteins comprise a large family of structurally related molecules, many of which form pores involved in host immunity and bacterial pathogenesis. Based on structural homology with CDCs, it is predicted that these regions comprise the MAC pore as well
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
