Alamethicin
Disrupts the Cholesterol Distribution
in Dimyristoyl Phosphatidylcholine–Cholesterol
Lipid Bilayers
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Abstract
Cell membranes are complex mixtures
of lipids, proteins, and other
molecules that serve as active, semipermeable barriers between cells,
as well as between their internal organelles, and the surrounding
medium. Their compositions and structures are tightly regulated to
ensure proper function. Cholesterol is a key component in mammalian
cellular membranes, where it serves to maintain membrane fluidity
and permeability. Here, the interaction of alamethicin, a 20 amino
acid residue peptide that creates transmembrane pores in lipid bilayer
membranes in a concentration-dependent manner, with bilayer membranes
composed of dimyristoyl phosphatidylcholine (DMPC) and cholesterol
(Chol) was studied. Small-angle neutron scattering (SANS) data demonstrate
that a low concentration of alamethicin (peptide-to-lipid ratio of
1/200) disrupts a lateral inhomogeneity seen in peptide-free DMPC:Chol
vesicles, which analysis of the SANS data indicates are Chol-rich
and Chol-poor phases having different thicknesses. Alamethicin disrupts
this structure, producing laterally homogeneous bilayers that are
thinner than either phase of the peptide-free bilayers, and possess
a strong asymmetry in the Chol content of the inner and outer bilayer
leaflets. The results suggest that a secondary membrane disruption
mechanism exists in parallel with the well-understood cytotoxic membrane
permeabilization that results when alamethcin forms transmembrane
pores. Specifically, the peptide can disrupt laterally organized lipidic
structures in cell membranes, as well as significantly perturb the
compositions of the inner and outer leaflets of the membrane. The
existence of a secondary mechanism of action against cellular membranes
for alamethicin raises the possibility that other membrane-active
peptides function similarly