Structural basis for lipid binding and function by an evolutionally conserved protein, Serum Amyloid A

Serum amyloid A (SAA) is a plasma protein that transports lipids during inflammation. To explore SAA solution conformations and lipid binding mechanism, we used hydrogen-deuterium exchange mass spectrometry, lipoprotein reconstitution, sequence analysis and molecular dynamics simulations. Solution conformations of lipid-bound and lipid-free mSAA1 at pH~7 agreed in details with the crystal structures but also showed important differences. The results revealed that amphipathic α-helices h1 and h3 comprise a lipid-binding site that is partially pre-formed in solution, is stabilized on lipoproteins, and shows lipid-induced folding of h3. This site sequesters apolar ligands via a concave hydrophobic surface in SAA oligomers. The largely disordered C-terminal region is conjectured to mediate promiscuous binding of other ligands. The h1-h2 linker region forms an unexpected β-hairpin that may represent an early amyloidogenic intermediate. The results establish structural underpinnings for understanding SAA interactions with lipids and other ligands, its evolutional conservation, and its transition to amyloid.