Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis

Serum amyloid A (SAA) is a major serum acute-phase protein and a cause of secondary amyloidosis, which impacts ∼1% of patients with chronic inflammation such as rheumatoid arthritis and neoplastic diseases. The lack of structural information has hampered our understanding of SAA-mediated amyloidosis and the development of effective therapies. Here we report a crystal structure of human SAA1.1 as a prototypic member of the family. SAA1.1 exists as a hexamer with subunits displaying a unique four-helix bundle fold. We further defined binding sites for heparin and high-density lipoprotein, identified major amyloidogenic epitopes, and visualized SAA-mediated protofibril formation using electron microscopy. These studies provide mechanistic insights into amyloidogenic conformational transition of SAA.