© 1997 American Heart Association, Inc.
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Design of a New Class of Amphipathic Helical Peptides for the Plasma Apolipoproteins That Promote Cellular Cholesterol Efflux But Do Not Activate LCAT
From Innogenetics NV, Gent (C.L.); Facultés Agronomiques de Gembloux (L.L., R.B.); the Laboratory of Lipoprotein Chemistry, Department of Biochemistry, University Gent (C.L., B.V., M.R.); and the Interdisciplinary Research Center, Katholieke Universiteit Leuven Afdeling K, Kortrijk (J.B.), Belgium.
Correspondence to Christine Labeur, Laboratory of Lipoprotein Chemistry, Department of Biochemistry, University Gent, Hospitaalstraat 13, 9000 Gent, Belgium. E-mail christine.labeur{at}rug.ac.be.
Abstract Amphipathic helical peptides represent the
lipid-binding units of the soluble plasma apolipoproteins. Several
synthetic peptide analogues have been designed to mimic such structures
and have been used to unravel some of the mechanisms involved in the
physiological function of the apolipoproteins, including lipid binding,
LCAT activation, and enhancement of cholesterol efflux from lipid-laden
cells. A series of novel synthetic peptides, named ID peptides,
was modeled on the basis of the structural properties common to the
amphipathic helices of apolipoprotein (apo) A-I. In these new peptides,
however, the segregation between hydrophobic and hydrophilic faces of
the helices is more pronounced than in apoA-I, so that the surface of
the hydrophobic and hydrophilic faces of the amphipathic helices is
equal. Moreover, there are fewer negatively charged residues in the
center of the hydrophilic face of the helical peptides. Most charged
amino acids are located along the edge of the helix and are susceptible
to forming salt bridges with residues of an antiparallel helix, such as
around a discoidal phospholipid/peptide complex. The physicochemical
characteristics of these peptides and their complexes with
phospholipids were compared with those of the 18A peptide and its
lipid/peptide complex. All ID peptides bind
dimyristoylphosphatidylcholine vesicles more rapidly than the 18A
peptide to yield discoidal peptide/phospholipid complexes of comparable
size. The 
-helical content of the lipid-free ID peptides is close to
that of the 18A peptide and increases slightly on lipid binding. The
stability of the ID and 18A peptides and of the phospholipid/peptide
complexes against guanidinium hydrochloride denaturation is higher than
that of lipid-free and lipid-bound apoA-I. LCAT activation by the
18A/phospholipid/cholesterol complexes equals that of
apoA-I/phospholipid/cholestrol complexes, whereas none of the ID
peptides tested is able to activate LCAT to a significant extent.
Incubation of the peptide/phospholipid complexes with lipid-laden
macrophages induces cellular cholesterol efflux and incorporation of
cholesterol into the complexes. The cholesterol efflux capacity of the
peptide/phospholipid complexes is comparable among the peptides and
higher than that of apoprotein/phospholipid complexes. In
conclusion, although the amphipathicity of the new peptides is higher
than that of the 18A model peptide, the lack of LCAT activation by the
ID peptides suggests that an enhanced segregation of the hydrophobic
and hydrophilic residues, equal magnitude of hydrophobic and
hydrophilic faces of the helix, and the absence of negatively charged
residues in the central part of the hydrophilic face might account for
the lack of LCAT activity of these peptides. These parameters do not
affect the capacity of the peptide/phospholipid complexes to promote
cellular cholesterol efflux.
Key Words: synthetic peptide • amphipathic helix • circular dichroism • cholesterol efflux • LCAT
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