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Nat Struct Mol Biol. 2017 Dec;24(12):1093-1099. doi: 10.1038/nsmb.3501. Epub 2017 Nov 13.

A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state.

Author information

1
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
2
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio, USA.
3
Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
5
Children's Hospital Oakland Research Institute, Oakland, California, USA.
6
Department of Medicine, Section on Endocrinology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
7
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
8
Department of Medicine, University of Washington, Seattle, Washington, USA.
9
Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA.
10
Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.

PMID:
29131142
PMCID:
PMC5749415
DOI:
10.1038/nsmb.3501
[Indexed for MEDLINE]
Free PMC Article

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