Structure of serum amyloid A suggests a mechanism for selective lipoprotein binding and functions: SAA as a hub in macromolecular interaction networks

Abstract

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 α-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 re-routing cholesterol transport. Our model is supported by the SAA cleavage in the inter-domain linker to generate the 1–76 fragment deposited in reactive amyloidosis. This model sheds new light on functions of this enigmatic protein.

Serum amyloid A self-assembles with phospholipids to form stable protein-rich nanoparticles with a distinct structure: A hypothetical function of SAA as a “molecular mop” in immune response

“…Our ultimate goal is to understand the delicate balance between the normal functions of SAA in innate immunity and lipid homeostasis and the pathologic pathway of SAA misfolding and deposition in AA amyloidosis. Both normal and pathologic effects of SAA are critically hinged upon its binding to numerous ligands, particularly lipids (Frame and Gursky, 2016; Kollmer et al, 2016; Tanaka et al, 2017) that are in the focus of the current study.…”

“…Notably, the radius of curvature of this surface, r ~4.2 nm, is commensurate with the HDL curvature. We proposed that this surface forms the lipid binding site in the SAA monomer, with a particular preference for HDL (Frame and Gursky, 2016). …”

“…in the absence of ligands under near-physiologic buffer conditions and temperatures it can be fully or partially unfolded depending on the species and the isoform. We postulated that helices h1 and h3 are folded when bound to the lipid surface, while other regions of the SAA molecule fold upon binding other ligands in a manner typical of other intrinsically disordered proteins (Frame and Gursky, 2016). …”

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

“…In addition, lipid binding sites in these proteins often overlap with the amyloid hot spots. Therefore, binding to a lipid surface protects these sensitive regions from the dangerous solvent exposure [3,44,47]. In contrast, free apolipoproteins are labile, since their low structural stability facilitates transient exposure of their amyloid hot spots [40].…”

Structure of serum amyloid A suggests a mechanism for selective lipoprotein binding and functions: SAA as a hub in macromolecular interaction networks

“…We used bioinformatics tools to perform amino acid sequence analysis of SAA family members [1] and combined the results with the atomic x-ray crystal structures of human SAA1.1 and murine SAA3 [2, 3]. This approach enabled us to identify a novel lipoprotein binding site in the SAA monomer whose shape explains, for the first time, the binding selectivity for HDL vis a vis larger lipoproteins.…”