Glycosaminoglycan-dependent Oligomerization and Fibrillogenesis of Serum Amyloid A

Serum amyloid A (SAA) is an inflammation-related protein that binds HDL and forms amyloid fibrils in the chronic inflammatory disease amyloid A (AA) amyloidosis. The C-terminus of SAA binds glycosaminoglycans (GAGs) and these ligands elicit different functionality for SAA. The role of GAGs in misfolding diseases appears to involve sulfation motifs as a key element in enhancing fibrillation. This study shows the divergent effects of GAGs on SAA oligomer folding and fibrillogenesis.  Folding experiments were monitored by analytical size exclusion chromatography (SEC), and surface plasmon resonance (SPR) was used to determine the binding constants of SAA and GAGs.  Fibrillation was corroborated by a fibril-detecting antibody assay and atomic force microscopy.  These studies support the view that amyloidogenic proteins are buttressed by GAGs in fibrillogenesis, putatively due to forming a negatively charged scaffold and aiding in the initial oligomer-fibril transformation demonstrated in these experiments.