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Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch

Elena Elimova^*,1, Robert Kisilevsky^*, and John B. Ancsin^*,2

^* Department of Biochemistry and

Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada; and the Syl and Molly Apps Research Centre, Kingston General Hospital, Kingston, Ontario, Canada

² Correspondence: Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada. E-mail: 3jba1{at}queensu.ca

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, E., Kisilevsky, R., Ancsin, J. B. Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.

Key Words: lipoprotein • amyloidosis • remodeling • acidic-pH binding site