Abstract

Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high-density lipoprotein (HDL) structure and metabolism, probably mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood, as lipid-free apoA-I has been notoriously resistant to high-resolution structural study. Published models from low-resolution techniques share certain features but vary considerably in shape and secondary structure. To tackle this central issue in lipoprotein biology, we assembled a team of structural biologists specializing in apolipoproteins and set out to build a consensus model of monomeric lipid-free human apoA-I. Combining novel and published cross-link constraints, small-angle X-ray scattering (SAXS), hydrogen–deuterium exchange (HDX) and crystallography data, we propose a time-averaged model consistent with much of the experimental data published over the last 40 years. The model provides a long-sought platform for understanding and testing details of HDL biogenesis, structure and function.

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Acknowledgements

This work was supported by an American Heart Association postdoctoral fellowship grant (16POST27710016 to J.T.M.), an National Institutes of Health Heart Lung and Blood Institute funded predoctoral fellowship to M.C. (HL125204-03), R01 GM098458 to W.S.D. and T.B.T., R01 HL112276 and HL127649 to M.G.S.-T., P01 HL026335 and R01 HL116518 to D.A., P01 HL12803 to W.S.D., J.P.S. and J.W.H. The MS data was acquired in the University of Cincinnati Proteomics Laboratory under the direction of K. Greis on a mass spectrometer funded in part through an NIH S10 shared instrumentation grant (RR027015 Gries-PI).

Author information

Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.

    • John T Melchior
    • , Allison L Cooke
    • , Jamie Morris
    • , Mark Castleberry
    •  & W Sean Davidson
  2. Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio, USA.

    • Ryan G Walker
    •  & Thomas B Thompson
  3. Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Martin K Jones
    • , Hyun D Song
    •  & Jere P Segrest
  4. School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.

    • Kerry-Anne Rye
  5. Children's Hospital Oakland Research Institute, Oakland, California, USA.

    • Michael N Oda
  6. Department of Medicine, Section on Endocrinology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

    • Mary G Sorci-Thomas
  7. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

    • Michael J Thomas
  8. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Jay W Heinecke
  9. Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Xiaohu Mei
    •  & David Atkinson
  10. Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Sissel Lund-Katz
    •  & Michael C Phillips

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Contributions

J.T.M. and W.S.D. conceived and designed new experiments reported in this paper. J.T.M., R.G.W., A.L.C., J.M., M.C. and H.D.S. performed experiments. J.T.M., R.G.W., M.C., T.B.T., M.K.J., H.D.S., J.P.S., M.C.P. and W.S.D. analyzed data. J.T.M., M.C., T.B.T., M.K.J., H.D.S., K.-A.R., M.N.O., M.G.S.-T., M.J.T., J.W.H., X.M., D.A., J.P.S., S.L.-K., M.C.P. and W.S.D. derived the model. J.T.M., T.B.T., K.-A.R., M.N.O., M.G.S.-T., M.J.T., J.W.H., D.A., J.P.S., S.L.-K., M.C.P. and W.S.D. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to W Sean Davidson.

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