Journal
FEBS LETTERS
Volume 590, Issue 6, Pages 866-879Publisher
WILEY
DOI: 10.1002/1873-3468.12116
Keywords
acute-phase high-density lipoprotein; amino acid sequence and structural analyses; immune response and reactive AA amyloidosis; intrinsically disordered protein hub; reverse cholesterol transport and atherosclerosis
Funding
- National Institutes of Health [GM067260]
- T32 Training grant [HL007969]
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Serum amyloid A is a major acute- phase plasma protein that modulates innate immunity and cholesterol homeostasis. We combine sequence analysis with x-ray crystal structures to postulate that SAA acts as an intrinsically disordered hub mediating interactions among proteins, lipids and proteoglycans. A structural model of lipoprotein-bound SAA monomer is proposed wherein two alpha-helices from the N-domain form a concave hydrophobic surface that binds lipoproteins. A C-domain, connected to the N-domain via a flexible linker, binds polar/charged ligands including cell receptors, bridging them with lipoproteins and rerouting cholesterol transport. Our model is supported by the SAA cleavage in the interdomain linker to generate the 1-76 fragment deposited in reactive amyloidosis. This model sheds new light on functions of this enigmatic protein.
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