Coordination of Zn²⁺ and Cu²⁺ to the membrane disrupting fragment of amylin

Abstract

Amylin, a small peptide co-secreted from pancreatic β-cells together with insulin, is one of the hallmarks of type II diabetes. In the course of this disease, it misfolds into small oligomers or into an aggregated β-sheet amyloid fiber. The misfolding mechanism is not yet well understood, but it is clear that metal ions such as zinc and copper play an important role in the process. In this work, the coordination chemistry of Zn(2+) and Cu(2+) with the membrane-disrupting part of amylin (amylin1-19) is discussed. Cu(2+) alters the structure of amylin1-19 only locally, by binding to His18 imidazole and to three preceding amides at the N-terminal side of this residue. Zn(2+) binds to the imidazole of His18 and the amine group of Lys1, imposing a kink in the peptide between these residues. This zinc-induced kink might be a partial explanation of the formation of prefibrillar oligomeric aggregates of amylin, which are much more toxic to β-cells than large fibrillar deposits.

New Insight in Copper‐Ion Binding to Human Islet Amyloid: The Contribution of Metal‐Complex Speciation To Reveal the Polypeptide Toxicity

“…The synthesis of some hIAPP PEG‐ylated peptide fragments that encompass the main metal‐ion binding site of His18 has allowed us to determine the affinity and speciation of different copper(II) complexes, thus mimicking the hIAPP behaviour. Accurate speciation has contributed to the assessment of Cu 2+ –IAPP binding and to the resolution of recent conflicting suggestions about the amino acid sequence involved in the metal‐ion interaction . Taken together, our data indicate the involvement of the residues that precede His18, thus favouring amino acid peptide deprotonation toward the N terminus.…”

Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance

“…Using more advanced EPR methods or specific site labeling would help on the elucidation of the structure for Cu(II)-hIAPP complexes. In addition, Rowińska-Żyrek [100] has researched the coordination of Cu(II) and Zn(II) to the monomeric form of the membrane disrupting fragment of the peptide, which compromises residues 1-19. With a 4N (1N im and 3N N- ), besides His18 being crucial, the coordination mode is forced towards the N-terminal as only one amide is available after His18.…”

“…3.B, left). For the membrane disrupting fragment, hIAPP(1-19), the N-terminal amine, together with the N im of His18 and 2 molecules of water coordinate zinc at physiological pH [100] (Fig. 3.B, right).…”

Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations

“…54) and to the three preceding amides at the N-terminal side of His18 (ref. 52) and at Lys1. 55 An opposite effect was observed for Al 3+ and Zn 2+ at the same concentration levels.…”

“…In general, it has been reported that Zn 2+ ion binds to amylin at the imidazole ring of His18 and the amine group of Lys1. 51,52 At low Zn 2+ concentrations (100 mM) and in the early stages of aggregation (40 min), Zn 2+ induces the formation of even larger Zn 2+ -amylin aggregates than those formed at high concentrations of Zn 2+ . During the nal stages of aggregation (when the amylin brils are formed), ber formation is inhibited at low concentrations of Zn 2+ and accelerated at higher concentrations.…”