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J. Biol. Chem., Vol. 276, Issue 44, 40949-40954, November 2, 2001
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From the Apolipoprotein (apo) E contains two
structural domains, a 22-kDa (amino acids 1-191) N-terminal domain and
a 10-kDa (amino acids 223-299) C-terminal domain. To better understand
apoE-lipid interactions on lipoprotein surfaces, we determined the
thermodynamic parameters for binding of apoE4 and its 22- and 10-kDa
fragments to triolein-egg phosphatidylcholine emulsions using a
centrifugation assay and titration calorimetry. In both large (120 nm)
and small (35 nm) emulsion particles, the binding affinities decreased
in the order 10-kDa fragment
Lipid Binding-induced Conformational Change in Human
Apolipoprotein E
EVIDENCE FOR TWO LIPID-BOUND STATES ON SPHERICAL PARTICLES*
§,,,, and
Joseph Stokes, Jr., Research Institute, the
Children's Hospital of Philadelphia, University of Pennsylvania School
of Medicine, Philadelphia, Pennsylvania 19104-4318 and the
¶ Gladstone Institute of Cardiovascular Diseases, Cardiovascular
Research Institute, and Department of Pathology, University of
California, San Francisco, California 94141
34-kDa intact apoE4 > 22-kDa fragment, whereas the maximal binding capacity of intact apoE4
was much larger than those of the 22- and 10-kDa fragments. These
results suggest that at maximal binding, the binding behavior of intact apoE4 is different from that of each fragment and that the N-terminal domain of intact apoE4 does not contact lipid. Isothermal titration calorimetry measurements showed that apoE binding to emulsions was an
exothermic process. Binding to large particles is enthalpically driven,
and binding to small particles is entropically driven. At a low surface
concentration of protein, the binding enthalpy of intact apoE4 (
69
kcal/mol) was approximately equal to the sum of the enthalpies for the
22- and 10-kDa fragments, indicating that both the 22- and 10-kDa
fragments interact with lipids. In a saturated condition, however, the
binding enthalpy of intact apoE4 (39 kcal/mol) was less exothermic
and rather similar to that of each fragment, supporting the hypothesis
that only the C-terminal domain of intact apoE4 binds to lipid. We
conclude that the N-terminal four-helix bundle can adopt either open or closed conformations, depending upon the surface concentration of
emulsion-bound apoE.
*
This work was supported in part by National Institutes of
Health Grants HL56083 (to S. L. K.) and HL41633 (to K. H. W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Joseph Stokes,
Jr., Research Inst., Children's Hospital of Philadelphia,
Abramson Research Bldg., Suite 302, 3615 Civic Center Blvd.,
Philadelphia, PA 19104-4318. Tel.: 215-590-0587; Fax:
215-590-0583; E-mail: phillipsmi@email.chop.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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