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Human islet amyloid polypeptide (hIAPP) is a molecule cosecreted in pancreatic \u03b2\u2005cells and represents the main constituent of an aggregated amyloid found in individuals affected by T2D. The trace\u2010element serum level is significantly influenced during the development of diabetes. In particular, the dys\u2010homeostasis of Cu<jats:sup>2+<\/jats:sup> ions may adversely affect the course of the disease. Conflicting results have been reported on the protective role played by complex species formed by Cu<jats:sup>2+<\/jats:sup> ions with hIAPP or its peptide fragments in vitro. The histidine (His) residue at position 18 represents the main binding site for the metal ion, but contrasting results have been reported on other residues involved in metal\u2010ion coordination, in particular those toward the N or C\u2005terminus. Sequences that encompass regions 17\u201329 and 14\u201322 were used to discriminate between the two models of the hIAPP coordination mode. Due to poor solubility in water, poly(ethylene glycol) (PEG) derivatives were synthesized. A peptide fragment that encompasses the 17\u201329 region of rat amylin (rIAPP) in which the arginine residue at position 18 was substituted by a histidine residue was also obtained to assess that the PEG moiety does not alter the peptide secondary structure. The complex species formed by Cu<jats:sup>2+<\/jats:sup> ions with Ac\u2010PEG\u2010hIAPP(17\u201329)\u2010NH<jats:sub>2<\/jats:sub>, Ac\u2010rIAPP(17\u201329)R18H\u2010NH<jats:sub>2<\/jats:sub>, and Ac\u2010PEG\u2010hIAPP(14\u201322)\u2010NH<jats:sub>2<\/jats:sub> were studied by using potentiometric titrations coupled with spectroscopic methods (UV\/Vis, circular dichroism, and EPR). The combined thermodynamic and spectroscopic approach allowed us to demonstrate that hIAPP is able to bind Cu<jats:sup>2+<\/jats:sup> ions starting from the His18 imidazole nitrogen atom toward the N\u2010terminus domain. The stability constants of copper(II) complexes with Ac\u2010PEG\u2010hIAPP(14\u201322)\u2010NH<jats:sub>2<\/jats:sub> were used to simulate the different experimental conditions under which aggregate formation and oxidative stress of hIAPP has been reported. Speciation unveils: 1)\u2005the protective role played by increased amounts of Cu<jats:sup>2+<\/jats:sup> ions on the hIAPP fibrillary aggregation, 2)\u2005the effect of adventitious trace amounts of Cu<jats:sup>2+<\/jats:sup> ions present in phosphate\u2010buffered saline (PBS), and 3)\u2005a reducing fluorogenic probe on H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> production attributed to the polypeptide alone.<\/jats:p>","DOI":"10.1002\/chem.201602816","type":"journal-article","created":{"date-parts":[[2016,8,5]],"date-time":"2016-08-05T05:12:43Z","timestamp":1470373963000},"page":"13287-13300","source":"Crossref","is-referenced-by-count":20,"title":["New Insight in Copper\u2010Ion Binding to Human Islet Amyloid: The Contribution of Metal\u2010Complex Speciation To Reveal the Polypeptide Toxicity"],"prefix":"10.1002","volume":"22","author":[{"given":"Antonio","family":"Magr\u00ec","sequence":"first","affiliation":[{"name":"Consiglio Nazionale delle Ricerche Istituto di Biostrutture e Bioimmagini  Via P. 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