Intrinsic Stability, Oligomerization, and Amyloidogenicity of HDL-Free Serum Amyloid A.

Abstract

Serum amyloid A (SAA) is an acute-phase reactant protein predominantly bound to high-density lipoprotein in serum and presumed to play various biological and pathological roles. Upon tissue trauma or infection, hepatic expression of SAA increases up to 1,000 times the basal levels. Prolonged increased levels of SAA may lead to amyloid A (AA) amyloidosis, a usually fatal systemic disease in which the amyloid deposits are mostly comprised of the N-terminal 1-76 fragment of SAA. SAA isoforms may differ across species in their ability to cause AA amyloidosis, and the mechanism of pathogenicity remains poorly understood. In vitro studies have shown that SAA is a marginally stable protein that folds into various oligomeric species at 4 °C. However, SAA is largely disordered at 37 °C, reminiscent of intrinsically disordered proteins. Non-pathogenic murine (m)SAA2.2 spontaneously forms amyloid fibrils in vitro at 37 °C whereas pathogenic mSAA1.1 has a long lag (nucleation) phase, and eventually forms fibrils of different morphology than mSAA2.2. Remarkably, human SAA1.1 does not form mature fibrils in vitro. Thus, it appears that the intrinsic amyloidogenicity of SAA is not a key determinant of pathogenicity, and that other factors, including fibrillation kinetics, ligand binding effects, fibril stability, nucleation efficiency, and SAA degradation may play key roles. This chapter will focus on the known structural and biophysical properties of SAA and discuss how these properties may help better understand the molecular mechanism of AA amyloidosis.