title: Divergent effect of glycosaminoglycans on the in vitro aggregation of serum amyloid A.
abstract: Serum amyloid A (SAA) is an apolipoprotein involved in poorly understood roles in inflammation. Upon trauma, hepatic expression of SAA rises 1000 times the basal levels. In the case of inflammatory diseases like rheumatoid arthritis, there is a risk for deposition of SAA fibrils in various organs leading to Amyloid A (AA) amyloidosis. Although the amyloid deposits in AA amyloidosis accumulate with the glycosaminoglycan (GAG) heparan sulfate, the role GAGs play in the function and pathology of SAA is an enigma. It has been shown that GAG sulfation is a contributing factor in protein fibrillation and for co-aggregating with a plethora of amyloidogenic proteins. Herein, the effects of heparin, heparan sulfate, hyaluronic acid, chondroitin sulfate A, and heparosan on the oligomerization and aggregation properties of pathogenic mouse SAA1.1 were investigated. Delipidated SAA was used to better understand the interactions between SAA and GAGs without the complicating involvement of lipids. The results revealed-to varying degrees-that all GAGs accelerated SAA1.1 aggregation, but had variable effects on its fibrillation. Heparan sulfate, hyaluronic acid, and heparosan did not affect much the fibrillation of SAA1.1. In contrast, chondroitin sulfate A blocked SAA fibril formation and facilitated the formation of spherical aggregates of various sizes. Interestingly, heparin caused formation of spherical SAA1.1 aggregates of various sizes, vast amounts of thin protofibrils, and few long fibrils of various heights. These results suggest that GAGs may have an intrinsic and divergent influence on the aggregation and fibrillation of HDL-free SAA1.1 in vivo, with functional and pathological implications.
authors.affiliation: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Aguilera
authors.affiliation: Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Beaudet
authors.affiliation: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.affiliation: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. Electronic address: colonw@rpi.edu.
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Colón
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006025:Glycosaminoglycans / Q000378:metabolism / Q000494:pharmacology*; D006493:Heparin / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055503:Protein Multimerization / Q000187:drug effects*; D058849:Protein Refolding / Q000187:drug effects; D017433:Protein Structure, Secondary; D000685:Serum Amyloid A Protein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein; D006493:Heparin
keywords: Fibrillation kinetics; GAGs; Inflammation; Reactive amyloidosis