Journal
JOURNAL OF STRUCTURAL BIOLOGY
Volume 200, Issue 3, Pages 293-302Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2017.06.007
Keywords
Protein-lipid surface interactions; Lipoprotein structure,function and stability; Lipid homeostasis in acute-phase response; Clearance of dead cells and cell repair; Lipoprotein remodeling, fusion and fission; Thermodynamic and kinetic stability
Funding
- National Institutes of Health [RO1 GM067260, T32 HL007969]
- Stevens Family Amyloid Endowment Fund
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Serum amyloid A (SAA) is an acute-phase protein whose action in innate immunity and lipid homeostasis is unclear. Most circulating SAA binds plasma high-density lipoproteins (HDL) and reroutes lipid transport. In vivo SAA binds existing lipoproteins or generates them de novo upon lipid uptake from cells. We explored the products of SAA-lipid interactions and lipoprotein remodeling in vitro. SAA complexes with palmitoyl-oleoyl phosphocholine (POPC) were analyzed for structure and stability using circular dichroism and fluorescence spectroscopy, electron microscopy, gel electrophoresis and gel filtration. The results revealed the formation of 8-11 nm lipoproteins that were similar to 50% alpha-helical and stable at near-physiological conditions but were irreversibly remodeled at T-m similar to 52 degrees C. Similar HDL-size nanoparticles formed spontaneously at ambient conditions or upon thermal remodeling of parent lipoproteins containing various amounts of proteins and lipids, including POPC and cholesterol. Therefore, such HDL-size particles formed stable kinetically accessible structures in a wide range of conditions. Based on their size and stoichiometry, each particle contained about 12 SAA and 72 POPC molecules, with a protein:lipid weight ratio circa 2.5:1, suggesting a structure distinct from HDL. High stability of these nanoparticles and their HDL-like size suggest that similar lipoproteins may form in vivo during inflammation or injury when SAA concentration is high and membranes from dead cells require rapid removal. We speculate that solubilization of membranes by SAA to generate lipoproteins in a spontaneous energy-independent process constitutes the primordial function of this ancient protein, providing the first line of defense in clearing cell debris from the injured sites. (c) 2017 Elsevier Inc. All rights reserved.
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