Thermodynamic surprises of Cu(II)–amylin analogue complexes in membrane mimicking solutions

Abstract

Membrane environment often has an important effect on the structure, and therefore also on the coordination mode of biologically relevant metal ions. This is also true in the case of Cu(II) coordination to amylin analogues—rat amylin, amylin1–19, pramlintide and Ac-pramlintide, which offer N-terminal amine groups and/or histidine imidazoles as copper(II) anchoring sites. Complex stabilities are comparable, with the exception of the very stable Cu(II)–amylin1–19, which proves that the presence of the amylin C-terminus lowers its affinity for copper(II); although not directly involved, its appropriate arrangement sterically prevents early metal binding. Most interestingly, in membrane-mimicking solution, the Cu(II) affinities of amylin analogues are lower than the ones in water, probably due to the crowding effect of the membrane solution and the fact that amide coordination occurs at higher pH, which happens most likely because the α-helical structure, imposed by the membrane-mimicking solvent, prevents the amides from binding at lower pH, requiring a local unwinding of the α-helix.

Zn(II) binding to pramlintide results in a structural kink, fibril formation and antifungal activity

“…Rat amylin binds Cu(II) via the N-terminal amine and three neighbouring amide nitrogens (toward the C-terminus) 21 , while the N-terminally acetylated pramlintide binds Cu(II) to the His18 imidazole nitrogen and three preceding amide nitrogens 32 . Cu(II) binding to pramlintide is a combination of the two coordination modes described above, which are in equilibrium with each other: Cu(II) binds either to the N-terminal amine and the next three amides (Fig.…”

Effect of Zn(II) on pramlintide: structural kink, fibril formation, antifungal activity

“…Rat amylin binds Cu(II) via the N-terminal amine and three neighbouring amide nitrogens (toward the Cterminus), 21 while the N-terminally acetylated pramlintide binds Cu(II) to the His18 imidazole nitrogen and three preceding amide nitrogens. 32 Cu(II) binding to pramlintide is a combination of the two coordination modes described above, which are in equilibrium with each other: Cu(II) binds either to the N-terminal amine and the next three amides (Figure 2B), or the His18 imidazole and three preceding amide nitrogens (Figure 2C). 21…”

Unveiling the Effects of Copper Ions in the Aggregation of Amyloidogenic Proteins

“…Various amyloidogenic peptides and their variants have been intensely investigated for their coordination sites with Cu + or Cu 2+ , but not to an equal extent. Among these peptides, Aβ has been the most extensively examined, followed by αSyn and IAPP [ 11 , 12 , 13 , 14 , 15 ]. On the other hand, tau and other amyloid proteins have a smaller amount of information available regarding their interactions with metal ions [ 16 , 17 , 18 ].…”