{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T02:03:20Z","timestamp":1792461800535,"version":"4.5.0"},"reference-count":43,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,11,26]],"date-time":"2013-11-26T00:00:00Z","timestamp":1385424000000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopolymers"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Glycosaminoglycans (GAGs) are found in association with virtually all extracellular protein deposits related to amyloid diseases. Particularly, GAGs were shown to enhance fibrillogenesis of the islet amyloid polypeptide (IAPP), a peptide hormone whose aggregation is associated with Type\u2010II diabetes pathogenesis. However, the exact molecular mechanism by which GAGs enhance IAPP amyloidogenesis remains unclear as well as the implications of cell surface GAGs in IAPP\u2010mediated cytotoxicity. The aim of this study was to gain conformational and thermodynamics insights about GAGs\u2010IAPP interactions as a function of IAPP protonation state and buffer ionic strength as well as to explore the roles of cell surface GAGs in IAPP cytotoxicity. Isothermal titration calorimetry revealed that protonation of residue His<jats:sup>18<\/jats:sup> increases the binding affinity of IAPP towards heparin and, in turn, strongly stimulates fibrillogenesis. Interaction of IAPP with heparin induces a random coil to helix conformational conversion and the helical intermediates could be on\u2010pathway to amyloid fibrils formation. Using rat beta\u2010cells INS\u20101 that were enzymatically treated with GAG lyases and a CHO cell line that is deficient in the biosynthesis of GAGs, we observed that the lack of GAGs at the plasma membrane does not prevent IAPP\u2010induced toxicity, whereas the presence of soluble heparin in the cell media inhibits IAPP cytotoxicity. Overall, this study reinforces the postulate that sulfated GAGs are actively implicated in IAPP amyloidogenic process <jats:italic>in vivo<\/jats:italic>, where they could play a protective role by interacting with cytotoxic species and converting them into less culprit amyloid fibrils. \u00a9 2013 Wiley Periodicals, Inc. 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