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J. Biol. Chem., Vol. 283, Issue 17, 11541-11549, April 25, 2008

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An Amphipathic Helical Region of the N-terminal Barrel of Phospholipid Transfer Protein Is Critical for ABCA1-dependent Cholesterol Efflux^*

John F. Oram¹, Gertrud Wolfbauer, Chongren Tang, W. Sean Davidson, and John J. Albers²

From the Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Box 356426, University of Washington, Seattle, Washington 98195 and the Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45237-0507

Phospholipid lipid transfer protein (PLTP) mimics high-density lipoprotein apolipoproteins in removing cholesterol and phospholipids from cells through the ATP-binding cassette transporter A1 (ABCA1). Because amphipathic -helices are the structural determinants for ABCA1 interactions, we examined the ability of synthetic peptides corresponding to helices in PLTP to remove cellular cholesterol by the ABCA1 pathway. Of the seven helices tested, only one containing PLTP residues 144–163 (p144), located at the tip of the N-terminal barrel, promoted ABCA1-dependent cholesterol efflux and stabilized ABCA1 protein. Mutating methionine 159 (Met-159) in this helix in PLTP to aspartate (M159D) or glutamate (M159E) nearly abolished the ability of PLTP to remove cellular cholesterol and dramatically reduced PLTP binding to phospholipid vesicles and its phospholipid transfer activity. These mutations impaired PLTP binding to ABCA1-generated lipid domains and PLTP-mediated stabilization of ABCA1 but increased PLTP binding to ABCA1. PLTP interactions with ABCA1 also mimicked apolipoproteins in activating Janus kinase 2; however, the M159D/E mutants were also able to activate this kinase. Structural analyses showed that the M159D/E mutations had only minor effects on PLTP conformation. These findings indicate that PLTP helix 144–163 is critical for removing lipid domains formed by ABCA1, stabilizing ABCA1 protein, interacting with phospholipids, and promoting phospholipid transfer. Direct interactions with ABCA1 and activation of signaling pathways likely involve other structural determinants of PLTP.

Received for publication, January 7, 2008 , and in revised form, February 15, 2008.

^* This work was supported by National Institutes of Health Grants P01HL030086, R01HL055362, RO1HL085437, and R01HL62542. 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.

¹ To whom correspondence may be addressed. Tel.: 206-543-3470; Fax: 206-685-3781; E-mail: joram{at}u.washington.edu. ² To whom correspondence may be addressed. Tel.: 206-685-3330; Fax: 206-685-3279; E-mail: jja{at}u.washington.edu.

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