Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.
During inflammatory diseases, serum amyloid A (SAA), an acute-phase apolipoprotein of HDL, can assemble into tissue deposits called AA amyloids. The mechanism and physiological factors promoting amyloidosis are largely unknown but likely involve heparan sulfate (HS), a glycosaminoglycan colocalized with all types of amyloids. In this study, we explored HDL-SAA:HS interactions using in vitro and cell culture assays to identify HS-binding domains that promote the conversion of native SAA into AA amyloid. HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates. A sequence motif in SAA responsible for this conversion was identified that contains a pH-sensitive heparin/HS-binding site, functions as a ligand for a cell surface receptor, and acts as a structural focal point for SAA aggregation. Synthetic peptides corresponding to this region promoted the deposition of AA amyloid in a monocyte culture model for AA amyloidogenesis. The effects were peptide sequence specific and reliant on the protonation of H36. We conclude that a highly conserved motif required for SAA binding to macrophages can, under acidic pH conditions and in an HS-dependent manner, also act as a molecular switch, directing SAA misfolding into AA amyloid. Similar histidine-dependent HS-binding sites are also found in other amyloidogenic polypeptides.
Elimova
Elena
E
Department of Biochemistry, Queen's University, Kingston, ON K7L 3N6, Canada.
Kisilevsky
Robert
R
Ancsin
John B
JB
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D006497:Heparan Sulfate / Q000378:metabolism*; D006639:Histidine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D006497:Heparan Sulfate; D006639:Histidine; D008075:Lipoproteins, HDL; D010455:Peptides; D000685:Serum Amyloid A Protein