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 SAAaggregation. 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, E., Kisilevsky, R., Ancsin, J. B. Heparan sulfate promotes the aggregation of HDL‐associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch. FASEB J . 23, 3436–3448 (2009). www.fasebj.org