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J. Biol. Chem., Vol. 278, Issue 26, 23227-23232, June 27, 2003

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Domain Structure and Lipid Interaction in Human Apolipoproteins A-I and E, a General Model^*

Hiroyuki Saito , Padmaja Dhanasekaran , David Nguyen , Paul Holvoet ¶, Sissel Lund-Katz  and Michael C. Phillips  ||

From the National Institute of Health Sciences, Osaka Branch, Osaka 540-0006, Japan, the Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Abramson Research Center, Philadelphia, Pennsylvania 19104-4318, and the ^¶Center for Experimental Surgery and Anesthesiology, University of Leuven, B-3000 Leuven, Belgium

Detailed structural information on human exchangeable apolipoproteins (apo) is required to understand their functions in lipid transport. Using a series of deletion mutants that progressively lacked different regions along the molecule, we probed the structural organization of lipid-free human apoA-I and the role of different domains in lipid binding, making comparisons to apoE, which is a member of the same gene family and known to have two structural domains. Measurements of -helix content by CD in conjunction with tryptophan and 8-anilino-1-naphthalenesulfonic acid fluorescence data demonstrated that deletion of the amino-terminal or central regions disrupts the tertiary organization, whereas deletion of the carboxyl terminus has no effect on stability and induces a more cooperative structure. These data are consistent with the lipid-free apoA-I molecule being organized into two structural domains similar to apoE; the amino-terminal and central parts form a helix bundle, whereas the carboxyl-terminal -helices form a separate, less organized structure. The binding of the apoA-I variants to lipid emulsions is modulated by reorganization of the helix bundle structure, because the rate of release of heat on binding is inversely correlated with the stability of the helix bundle. Based on these observations, we propose that there is a two-step mechanism for lipid binding of apoA-I: apoA-I initially binds to a lipid surface through amphipathic -helices in the carboxyl-terminal domain, followed by opening of the helix bundle in the amino-terminal domain. Because apoE behaves similarly, this mechanism is probably a general feature for lipid interaction of other exchangeable apolipoproteins, such as apoA-IV.

Received for publication, April 1, 2003 , and in revised form, April 21, 2003.

^* This work was supported by National Institutes of Health Grants HL22633 and HL56083, the Belgian Interuniversitaire Attractiepolen Programma (P05/02), and Grant-in-aid for Scientific Research 14572045 from the Japan Society for the Promotion of Science. 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 Institute, The 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{at}email.chop.edu.

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