The copper-binding features of rat islet amyloid polypeptide (r-IAPP) are herein disclosed through the determination of the stability constants and spectroscopic properties of its copper complex species. To mimic the metal binding sites of the human IAPP (h-IAPP), a soluble, single-point mutated variant of r-IAPP, having a histidine residue in place of Arg18, was synthesized, that is, r-IAPP(1-37; R18H). The peptide IAPP(1-8) was also characterized to have deeper insight into the N-terminus copper(II)-binding features of r-IAPP as well as of its mutated form. A combined experimental (thermodynamic and spectroscopic) and computational approach allowed us to assess the metal loading and the coordination features of the whole IAPP. At physiological pH, the N-terminal amino group is the Cu2+main binding site both of entire r-IAPP and of its mutated form that mimics h-IAPP. The histidine residue present in this mutated polypeptide accounts for the second Cu2+binding. We can speculate that the copper driven toxicity of h-IAPP in comparison to that of r-IAPP can be attributed to the different metal loading and the presence of a second metal anchoring site, the His18, whose role is usually invoked in the process of h-IAPP aggregation.

From Peptide Fragments to Whole Protein: Copper(II) Load and Coordination Features of IAPP

La Mendola, Diego;
2017

Abstract

The copper-binding features of rat islet amyloid polypeptide (r-IAPP) are herein disclosed through the determination of the stability constants and spectroscopic properties of its copper complex species. To mimic the metal binding sites of the human IAPP (h-IAPP), a soluble, single-point mutated variant of r-IAPP, having a histidine residue in place of Arg18, was synthesized, that is, r-IAPP(1-37; R18H). The peptide IAPP(1-8) was also characterized to have deeper insight into the N-terminus copper(II)-binding features of r-IAPP as well as of its mutated form. A combined experimental (thermodynamic and spectroscopic) and computational approach allowed us to assess the metal loading and the coordination features of the whole IAPP. At physiological pH, the N-terminal amino group is the Cu2+main binding site both of entire r-IAPP and of its mutated form that mimics h-IAPP. The histidine residue present in this mutated polypeptide accounts for the second Cu2+binding. We can speculate that the copper driven toxicity of h-IAPP in comparison to that of r-IAPP can be attributed to the different metal loading and the presence of a second metal anchoring site, the His18, whose role is usually invoked in the process of h-IAPP aggregation.
Magrì, Antonio; Pietropaolo, Adriana; Tabbì, Giovanni; La Mendola, Diego; Rizzarelli, Enrico
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/885112
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