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J. Biol. Chem., Vol. 281, Issue 10, 6511-6519, March 10, 2006

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Association of a Model Class A (Apolipoprotein) Amphipathic Helical Peptide with Lipid

HIGH RESOLUTION NMR STUDIES OF PEPTIDE·LIPID DISCOIDAL COMPLEXES^*

Vinod K. Mishra¹, G. M. Anantharamaiah, A principal in Bruin Pharma, a startup biotechnology company², Jere P. Segrest, Mayakonda N. Palgunachari, Manjula Chaddha, S. W. Simon Sham, and N. Rama Krishna³

From the The Atherosclerosis Research Unit, Department of Medicine, and Department of Biochemistry and Molecular Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham Medical Center, Birmingham, Alabama 35294

Class A amphipathic helical peptides have been shown to mimic apolipoprotein A-I, the major protein component of high density lipoproteins and have been shown to inhibit atherosclerosis in several dyslipidemic mouse models. Previously we reported the NMR structure of Ac-18A-NH₂, the base-line model class A amphipathic helical peptide in a 50% (v/v) trifluoroethanol-d₃/water mixture, a membrane-mimic environment (Mishra, V. K., Palgunachari, M. N., Anantharamaiah, G. M., Jones, M. K., Segrest, J. P., and Krishna, N. R. (2001) Peptides 22, 567–573). The peptide Ac-18A-NH₂ forms discoidal nascent high density lipoprotein-like particles with 1,2-dimyristoyl-sn-glycero-3-phosphocholine. Because subtle structural changes in the peptide·lipid complexes have been shown to be responsible for their antiatherogenic properties, we undertook high resolution NMR studies to deduce detailed structure of recombinant peptide·1,2-dimyristoyl-sn-glycero-3-phosphocholine complexes. The peptide adopts a well defined amphipathic helical structure in association with the lipid at a 1:1 peptide:lipid weight ratio. Nuclear Overhauser effect spectroscopy revealed a number of intermolecular close contacts between the aromatic residues in the hydrophobic face of the helix and the lipid acyl chain protons. The pattern of observed peptide-lipid nuclear Overhauser effects is consistent with a parallel orientation of the amphipathic helix, with respect to the plane of the lipid bilayer, on the edge of the disc (the belt model). Based on the results of chemical cross-linking and molecular modeling, we propose that peptide helices are arranged in a head to tail fashion to cover the edge of the disc. This arrangement of peptides is also consistent with the pK_a values of the Lys residues determined previously. Taken together, these results provide for the first time a high resolution structural view of the peptide·lipid discoidal complexes formed by a class A amphipathic helical peptide.

Received for publication, October 21, 2005 , and in revised form, December 29, 2005.

The atomic coordinates and structure factors (codes 2FQ5 and 2FQ8) 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 in part by NHLBI Grant PO1 HL34343 and NCI Grant CA-13148 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material including Figs. 10 and 11.

¹To whom correspondence may be addressed: D806, 1808 Seventh Ave. S., University of Alabama at Birmingham Medical Center, Birmingham, AL 35294-0012. Tel.: 205-934-4021; Fax: 205-975-8079; E-mail: vmishra{at}uab.edu. ²To whom correspondence may be addressed: D668, 1808 Seventh Ave. S., University of Alabama at Birmingham Medical Center, Birmingham, AL 35294-0012. Tel.: 205-934-1884; Fax: 205-975-8079; E-mail: ananth{at}uab.edu. ³To whom correspondence may be addressed: CHSB-19 B-31, 933, 19th St. S., Birmingham, AL 35294-2041. Tel.: 205-934-5695; Fax: 205-934-6475; E-mail: NRKrishna{at}bmg.bhs.uab.edu.

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