The cholesterol-dependent cytolysins.

In view of the recent studies on the CDCs, a reasonable schematic of the stages leading to membrane insertion of the CDCs can be assembled. As shown in Fig. 3, we propose that the CDC first binds to the membrane as a monomer. These monomers then diffuse laterally on the membrane surface to encounter other monomers or incomplete oligomeric complexes. Presumably, once the requisite oligomer size is reached, the prepore complex is converted into the pore complex and a large membrane channel is formed. During the conversion of the prepore complex to the pore complex, we predict that the TMHs of the subunits in the prepore complex insert into the bilayer in a concerted fashion to form the large transmembrane beta-barrel, although this still remains to be confirmed experimentally. Many intriguing problems concerning the cytolytic mechanism of the CDCs remain unsolved. The nature of the initial interaction of the CDC monomer with the membrane is currently one of the most controversial questions concerning the CDC mechanism. Is cholesterol involved in this interaction, as previously assumed, or do specific receptors exist for these toxins that remain to be discovered? Also, the trigger for membrane insertion and the regions of these toxins that facilitate the [figure: see text] interaction of the monomers during prepore complex formation are unknown. In addition, the temporal sequence of the multiple structural changes that accompany the conversion of the soluble CDC monomer into a membrane-inserted oligomer have yet to be defined or characterized kinetically.