title: 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 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.
authors.affiliation: Department of Physiology & Biophysics, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Frame
authors.affiliation: Department of Physiology & Biophysics, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Gursky
mesh_terms: D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D000685:Serum Amyloid A Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D008074:Lipoproteins; D046912:Multiprotein Complexes; D000685:Serum Amyloid A Protein
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