Heparin accelerates gelsolin amyloidogenesis.
The chemical environment of the extracellular matrix may influence the tissue-selective deposition observed there in gelsolin amyloid disease. Previously, we have identified the proteases that generate the amyloidogenic fragments from the full-length gelsolin variants and demonstrated that heparin is capable of accelerating gelsolin amyloidogenesis. Herein, we identify the structural features of heparin that promote the 8 kDa disease-associated gelsolin fragments (residues 173-243) generated at the cell surface to form amyloid. In conjunction with electron microscopy analyses, our kinetic studies demonstrate that heparin efficiently accelerates the formation of gelsolin amyloid by enabling intermolecular beta-sheet formation. The use of heparin analogues reveals that sulfation is important in accelerating amyloidogenesis and that the extent of acceleration is proportional to the molecular weight of heparin. In addition, heparin accelerated aggregation at both early and late stages of amyloidogenesis. Dynamic light scattering coupled to size exclusion chromatography showed that heparin promotes the formation of soluble aggregates. Collectively, these data reveal that heparin templates fibril formation and affords solubility to the aggregating peptides through its sulfated structure. By extension, the biochemical results herein suggest that tissue-selective deposition characteristic of the gelsolin amyloidoses is likely influenced by the extracellular localization of distinct glycosaminoglycans.
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Ji Young
JY
Suk
Fuming
F
Zhang
William E
WE
Balch
Robert J
RJ
Linhardt
Jeffery W
JW
Kelly
D000682:Amyloid / Q000096:biosynthesis*; D000686:Amyloidosis / Q000503:physiopathology; D002850:Chromatography, Gel; D002942:Circular Dichroism; D018260:Gelsolin / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D017354:Point Mutation; D017433:Protein Structure, Secondary; D013056:Spectrophotometry, Ultraviolet
D000682:Amyloid; D018260:Gelsolin; D006493:Heparin