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* Joseph Stokes Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318
Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, Department of Pathology, University of California, San Francisco, CA 94141-9100
The Atherosclerosis Research Unit and Departments of Medicine and Biochemistry and Molecular Genetics, The University of Alabama at Birmingham Medical Center, Birmingham, AL 35294
2 To whom correspondence should be addressed. e-mail: katzs{at}email.chop.edu
We examined the effects of apolipoprotein E (apoE) domain structure and polymorphism on the kinetics of solubilization (clearance) of dimyristoyl-phosphatidylcholine multilamellar vesicles. This second order reaction consisted of two simultaneous kinetic phases; it also exhibited saturable kinetics when the apolipoprotein concentration was increased at a constant lipid concentration. Rigid connections between 
-helices in the 4-helix bundle formed by the 22 kDa N-terminal domain of apoE reduced the reaction rate. In contrast, the more flexible interhelical connections in apoA-I and the 10 kDa C-terminal domain of apoE promoted rapid solubilization of dimyristoyl-phosphatidylcholine (DMPC) multilamellar vesicles (mLV). Full-length apoE-3 reacted at about half the rate of the C-terminal domain alone. This decrease occurred because the hinge region probably decreased the interhelical flexibility of the 10 kDa domain and because both domains are conformationally restricted when covalently linked. Furthermore, the mLV surface affinities and reaction rates of the N-terminal domain fragments of the three common apoE isoforms tended to vary inversely with the stabilities of these fragments.
These results confirm the importance of apoE's structure on the kinetics of lipid interaction. They suggest that flexibility in an apolipoprotein molecule increases the time-averaged exposure of hydrophobic surface area, thereby increasing the rate of phospholipid solubilization.
Abbreviations: apo, apolipoprotein; DMPC, dimyristoyl-phosphatidylcholine; Gdn HCl, guanidine hydrochloride; ITC, isothermal titration calorimetry; LUV, large unilamellar vesicles; mLV, multilamellar vesicles; PC, phosphatidylcholine; PL, phospholipid; POPC, palmitoyl-oleoylphosphatidylcholine
Supplementary key words apolipoprotein • dimyristoyl-phosphatidylcholine • kinetics • protein-lipid interaction • turbidimetry
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