Heparin Accelerates Gelsolin Amyloidogenesis

Suk, J.Y.
Zhang, F.
Balch, W.E.
Linhardt, Robert J.
Kelly, J.W.
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Heparin Accelerates Gelsolin Amyloidogenesis, J. Y. Suk, F. Zhang, W. E. Balch, R. J. Linhardt, J. W. Kelly, Biochemistry, 45, 2234-2242, 2006.
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.
Biochemistry, 45, 2234-2242
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The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
American Chemical Society (ACS)
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
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