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The C-terminal domain of apolipoprotein A-I contains a lipid-sensitive conformational trigger

Nature Structural & Molecular Biology volume 10, pages 455–460 (2003)Cite this article

Abstract

Exchangeable apolipoproteins can convert between lipid-free and lipid-associated states. The C-terminal domain of human apolipoprotein A-I (apoA-I) plays a role in both lipid binding and self-association. Site-directed spin-label electron paramagnetic resonance spectroscopy was used to examine the structure of the apoA-I C terminus in lipid-free and lipid-associated states. Nitroxide spin-labels positioned at defined locations throughout the C terminus were used to define discrete secondary structural elements. Magnetic interactions between probes localized at positions 163, 217 and 226 in singly and doubly labeled apoA-I gave inter- and intramolecular distance information, providing a basis for mapping apoA-I tertiary and quaternary structure. Spectra of apoA-I in reconstituted HDL revealed a lipid-induced transition of defined random coils and β-strands into α-helices. This conformational switch is analogous to triggered events in viral fusion proteins and may serve as a means to overcome the energy barriers of lipid sequestration, a critical step in cholesterol efflux and HDL assembly.

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Figure 1: Secondary structure analysis of lipid-free apoA-I residues 163–241.
Figure 2: Tertiary arrangement of apoA-I secondary structures.
Figure 3: Comparison of lipid-free and lipid-bound apoA-I structure.
Figure 4: Lipid-induced conformational transition of apoA-I and fusogenic subunit HA2 from influenza hemagglutinin.

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Acknowledgements

We thank J. Crowe for his assistance with preliminary FTIR analyses. We would also like to thank B.J.S. Nitta for her critical advice and technical assistance, as well as C. Fang and C. Robertson for their valuable technical assistance. This work was supported by grants from NHLBI and American Heart Association, and by an award from the Pfizer Inc. Atorvastatin Research Awards Program.

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Authors and Affiliations

  1. Children's Hospital Oakland Research Institute, Oakland, 94609-1673, California, USA

    Michael N Oda & Robert O Ryan

  2. Life Sciences Division MS 1-222, Lawrence Berkeley National Laboratory, Berkeley, 94720, California, USA

    Trudy M Forte

  3. Department of Biological Chemistry, University of California, Davis, 95616, California, USA

    John C Voss

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  1. Michael N Oda
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Correspondence to Michael N Oda.

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Oda, M., Forte, T., Ryan, R. et al. The C-terminal domain of apolipoprotein A-I contains a lipid-sensitive conformational trigger. Nat Struct Mol Biol 10, 455–460 (2003). https://doi.org/10.1038/nsb931

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