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J. Biol. Chem., Vol. 280, Issue 28, 26477-26482, July 15, 2005
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From the
the Gladstone Institute of Neurological Disease, San Francisco, California 94158 and the Cardiovascular Research Institute and ¶Department of Pathology, University of California, San Francisco, California 94143
Apolipoprotein (apo) E4 is a major risk factor for Alzheimer and cardiovascular diseases. ApoE4 differs from the two other common isoforms (apoE2 and apoE3) by its lower resistance to denaturation and greater propensity to form partially folded intermediates. As a first step to determine the importance of stability differences in vivo, we reengineered a partially humanized variant of the amino-terminal domain of mouse apoE (T61R mouse apoE) to acquire a destabilized conformation like that of apoE4. For this process, we determined the crystal structure of wild-type mouse apoE, which, like apoE4, forms a four-helix bundle, and identified two structural differences in the turn between helices 2 and 3 and in the middle of helix 3 as potentially destabilizing sites. Introducing mutations G83T and N113G at these sites destabilized the mouse apoE conformation. The mutant mouse apoE more rapidly remodeled phospholipid than T61R mouse apoE, which supports the hypothesis that a destabilized conformation promotes apoE4 lipid binding.
Received for publication, April 11, 2005 , and in revised form, May 11, 2005.
The atomic coordinates and structure factors (code 1YA9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
* This work was supported by Grants P01 AG022074 and R01 AG020235 from the National Institutes of Health. 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.
** Both authors contributed equally to this work.
|| To whom correspondence should be addressed: Gladstone Institute of Neurological Disease, 1650 Owens St., San Francisco, CA 94158. Tel.: 415-734-2000; Fax: 415-355-0824; E-mail: kweisgraber{at}gladstone.ucsf.edu.
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