Fig. 7.

Schematic summary of the effects on pore formation of cholesterol and oxidation of the undecapeptide cysteine thiol. ILY and PFO D4 domains are depicted with membranes (gray). (Upper) After ILY binds to hCD59, the L1–L3 loops insert into the membrane in a cholesterol-dependent manner. This insertion is followed by the cholesterol-independent insertion of the undecapeptide residue Ala-486 of the undecapeptide with the subsequent formation of the pore. It is not known whether the tryptophan residues of the ILY undecapeptide insert into the membrane (they are not shown as inserted in the model). In the absence of cholesterol, Ala-486 of ILY inserts into the membrane after receptor binding, but loops L1–L3 do not, thus trapping ILY in the prepore complex. (Lower) Loops L1–L3, the undecapeptide tryptophan residues, and Cys-459 of PFO insert into the membrane in cholesterol-rich membranes. Preventing the insertion of any single L1–L3 loop prevents PFO binding to cholesterol-rich membranes, similar to the effect seen with membranes that lack cholesterol. Oxidation or modification of the Cys-459 thiol blocks membrane insertion of the undecapeptide tryptophan residues and traps PFO in the prepore complex.