Packing a punch: the mechanism of pore formation by cholesterol dependent cytolysins and membrane attack complex/perforin-like proteins

The bacterial cholesterol dependent cytolysins (CDCs) and membrane attack complex/perforin-like proteins (MACPF) represent two major branches of a large, exceptionally diverged superfamily. Most characterized CDC/MACPF proteins form large pores that function in immunity, venoms, and pathogenesis. Extensive structural, biochemical and biophysical studies have started to address some of the questions surrounding how the soluble, monomeric form of these remarkable molecules recognize diverse targets and assemble into oligomeric membrane embedded pores. This review explores mechanistic similarities and differences in how CDCs and MACPF proteins form pores.

► Structures of CDC and MACPF pore forming toxins show that they share a common topology.
► In CDCs, the common topology is involved in forming the transmembrane β-barrel (pore).
► The structural homology between CDC and MACPF proteins suggest they share an ancient evolutionary ancestor.
► The structural homology suggests that MACPF pore forming toxins may form β-barrel pores similar to CDCs.
► Differences in the pore assembly pathways are shown for CDS, perforin and the MAC.