SYM-42-03

Cholesterol-dependent cytolysins: from water-soluble state to membrane pore

SL Lawrence1, RK Tweten2, CJ Morton1 and MW Parker1,3

  1. St. Vincents Institute of Medical Research, Melbourne, Australia
  2. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  3. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Australia

Cholesterol-dependent cytolysins (CDCs) are a family of pore-forming toxins that punch holes in the outer membrane of eukaryotic cells. The CDCs exhibit a number of unique features amongst pore-forming toxins including an absolute dependence on the presence of cholesterol-rich membranes for their activity and the formation of oligomeric transmembrane pores greater than 15 nM in diameter. The first crystal structure of a CDC was that of perfringolysin O (1) and most of our understanding of CDC function is based on studies of this toxin (2,3). We have subsequently determined structures of other family members that have confirmed that the 3D fold first seen in PFO is shared by all family members (5-8). We have now determined a number of new CDC structures which are providing valuable insights into the role of receptor binding, oligomerisation and prepore assembly. The conversion from water-soluble monomer to pore is highly complex: it is essential that the pore does not form prematurely otherwise the target cell will not be successfully breached (9). The crystal structures of the water-soluble states of these toxins, together with cryo-electron microscopy, small angle X-ray scattering data, fluorescence spectroscopy and molecular dynamics simulations have proved very useful for modelling their membrane pores.
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