α-Hemolysin from Staphylococcus aureus: An archetype of β-barrel, channel-forming toxins

α-Hemolysin, secreted from Staphylococcus aureus as a water-soluble monomer of 33.2 kDa, assembles on cell membranes to form transmembrane, heptameric channels. The structure of the detergent-solubilized heptamer has been determined by X-ray crystallography to 1.9 Å resolution. The heptamer has a mushroom-like shape and measures up to 100 in diameter and 100 Å in height. Spanning the length of the molecule and coincident with the molecular sevenfold axis is a water-filled channel that ranges in diameter from ~16 to ~46 Å. A 14 strand antiparallel β-barrel, in which two strands are contributed by each subunit, defines the transmembrane domain. On the exterior of the β-barrel there is a hydrophobic belt approximately 30 Å in width that provides a surface complementary to the nonpolar portion of the lipid bilayer. The extensive protomer-protomer interfaces are composed of both salt-links and hydrogen bonds, as well as hydrophobic interactions, and these contacts provide a molecular rationalization for the stability of the heptamer in SDS solutions up to 65°C. With the structure of the heptamer in hand, we can better understand the mechanisms by which the assembled protein interacts with the membrane and can postulate mechanisms of assembly.