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J. Biol. Chem., Vol. 278, Issue 42, 40723-40729, October 17, 2003

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Effects of Polymorphism on the Lipid Interaction of Human Apolipoprotein E^*

Hiroyuki Saito , Padmaja Dhanasekaran , Faye Baldwin , Karl H. Weisgraber ¶, Michael C. Phillips  and Sissel Lund-Katz  ||

From the National Institute of Health Sciences, Osaka Branch, Osaka 540-0006, Japan, the Children's Hospital of Philadelphia, Abramson Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318, and the ^¶Gladstone Institute of Cardiovascular Diseases, Cardiovascular Research Institute, and the Department of Pathology, University of California, San Francisco, California 94141

ApoE exists as three common isoforms, apoE2, apoE3, and apoE4; apoE2 and apoE3 preferentially bind to high density lipoproteins, whereas apoE4 prefers very low density lipoproteins (VLDL). To understand the molecular basis for the different lipoprotein distributions of these isoforms in human plasma, we examined the lipid-binding properties of the apoE isoforms and some mutants using lipid emulsions. With both large (120 nm) and small (35 nm) emulsion particles, the binding affinity of apoE4 was much higher than that of apoE2 and apoE3, whereas the maximal binding capacities were similar among the three isoforms. The 22-kDa N-terminal fragment of apoE4 displayed a much higher binding capacity than did apoE2 and apoE3. The apoE4(E255A) mutant, which has no electrostatic interaction between Arg⁶¹ and Glu²⁵⁵, showed binding behavior similar to that of apoE3, indicating that N- and C-terminal domain interaction in apoE4 is responsible for its high affinity for lipid. In addition, the apoE3(P267A) mutant, which is postulated to contain a long -helix in the C-terminal domain, had significantly decreased binding capacities for both sizes of emulsion particle, suggesting that the apoE4 preference for VLDL is not due to a stabilized long -helical structure. Isothermal titration calorimetry measurements showed that there is no significant difference in thermodynamic parameters for emulsion binding among the apoE isoforms. However, fluorescence measurements of 8-anilino-1-naphthalenesulfonic acid binding to apoE indicated that apoE4 has more exposed hydrophobic surface compared with apoE3 mainly due to the different tertiary organization of the C-terminal domain. The less organized structure in the C-terminal domain of apoE4 leads to the higher affinity for lipid, contributing to its preferential association with VLDL. In fact, we found that apoE4 binds to VLDL with higher affinity compared with apoE3.

Received for publication, May 7, 2003 , and in revised form, August 5, 2003.

^* This work was supported in part by Grants HL56083 (to S. L.-K.) and AG20235 (to K. H. W.) from the National Institutes of Health, Grant-in-aid for Scientific Research 14572045 from the Japan Society for the Promotion of Sciences, and a grant from the Ono Medical Research Foundation (to H. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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.: 215-590-0588; Fax: 215-590-0583; E-mail: katzs{at}email.chop.edu.

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