Biophysical Society Thematic Meeting

Liposomes, Exosomes, and Virosomes: From Modeling Complex

Membrane Processes to Medical Diagnostics and Drug Delivery

Monday Speaker Abstracts

Membrane Pore-forming Proteins in the Molecular Arms Race Between Host and

Pathogen

Helen R. Saibil

Birkbeck, University of London, London, United Kingdom.

Pathogens have evolved weapons to invade and damage our cells, and our immune system has

evolved defences against these attacks. Among the weaponry used by both sides in this continual

war are proteins that punch holes in cell membranes. Membrane perforation enables pathogens to

take over host cells and resources for their own replication, and also enables host immune

systems to kill invading pathogens. The membrane attack complex-perforin (MACPF)/

cholesterol dependent cytolysin (CDC) superfamily of membrane pore-forming proteins is used

by a wide range of pathogens as well as by host immune systems.

The objective of the work is to understand the mechanisms by which MACPF and CDC proteins

convert from their soluble, monomeric forms into large, oligomeric arcs and rings that insert into

membranes and perforate them, without any external energy source. The structures of several

CDC and MACPF protein assemblies on liposomes have been determined by cryo electron

microscopy and single particle analysis; the dynamics of pore fomation were studied by atomic

force microscopy. Fluorescence microscopy and cellular electron tomography have been used to

study the actions of MACPF proteins i

n situ

. The findings reveal common features of the pore

forming mechanism in different members of the superfamily, invovling the opening of a bent and

twisted beta sheet and release of compact, helical clusters to assemble into an extended,

transmembrane beta barrel. Displacement of a helical motif positioned near the bend in the beta

sheet appears to be required to unlock the conformational change.