Reciprocal effects of apolipoprotein and lytic peptide analogs on membranes. Cross-sectional molecular shapes of amphipathic alpha helixes control membrane stability.
Apolipoprotein (class A) amphipathic helixes are postulated to act as detergents by virtue of their cross-section being wedge-shaped. Using computer analysis of naturally occurring class A and lytic (class L) amphipathic helixes, we designed two archetypical model peptides. Analogs of these two peptides, incorporating substitutions or modifications of interfacial or basic residues, had the following effects. Class A peptides stabilized bilayer structure, reduced leakage from large unilamellar vesicles and erythrocytes, and inhibited lysis induced by class L peptides. Class L peptides destabilized bilayer structure in model membranes and increased binding of class A peptides to erythrocytes. The ability of class L analogs to lyse membranes and induce inverted lipid phases was reduced by either decreasing the bulk of an interfacial residue, increasing the angle subtended by the polar face, or increasing the bulk of the basic residues. The ability of the class A analog to stabilize bilayer structure and inhibit erythrocyte lysis by class L peptides was enhanced by methylating the Lys residues. These results can be explained by a model that we term the reciprocal wedge hypothesis. By analogy to the reciprocal effects of phospholipid shapes on membrane structure, we propose that the wedge shape of class A helixes stabilizes membrane bilayers, whereas the inverted wedge shape of class L helixes destabilizes membrane bilayers, and, thus, one class will neutralize the effect of the other class on membranes.
Tytler
E M
EM
Department of Medicine, University of Alabama Medical Center, Birmingham 35294.
Segrest
J P
JP
Epand
R M
RM
Nie
S Q
SQ
Epand
R F
RF
Mishra
V K
VK
Venkatachalapathi
Y V
YV
Anantharamaiah
G M
GM
D000595:Amino Acid Sequence; D001054:Apolipoproteins A / Q000737:chemistry / Q000494:pharmacology*; D003196:Computer Graphics; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008051:Lipid Bilayers; D008555:Melitten / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation
D001054:Apolipoproteins A; D008051:Lipid Bilayers; D010455:Peptides; D008555:Melitten