A?5-x Peptides: N-Terminal Truncation Yields Tunable Cu(II) Complexes.

ABSTRACT: The A?5-x peptides (x = 38, 40, 42) are minor A? species in normal brains but elevated upon the application of inhibitors of A? processing enzymes. They are interesting from the point of view of coordination chemistry for the presence of an Arg-His metal binding sequence at their N-terminus capable of forming a 3-nitrogen (3N) three-coordinate chelate system. Similar sequences in other bioactive peptides were shown to bind Cu(II) ions in biological systems. Therefore, we investigated Cu(II) complex formation and reactivity of a series of truncated A?5-x peptide models comprising the metal binding site: A?5-9, A?5-12, A?5-12Y10F, and A?5-16. Using CD and UV-vis spectroscopies and potentiometry, we found that all peptides coordinated the Cu(II) ion with substantial affinities higher than 3 × 1012 M-1 at pH 7.4 for A?5-9 and A?5-12. This affinity was elevated 3-fold in A?5-16 by the formation of the internal macrochelate with the fourth coordination site occupied by the imidazole nitrogen of the His13 or His14 residue. A much higher boost of affinity could be achieved in A?5-9 and A?5-12 by adding appropriate amounts of the external imidazole ligand. The 3N Cu-A?5-x complexes could be irreversibly reduced to Cu(I) at about -0.6 V vs Ag/AgCl and oxidized to Cu(III) at about 1.2 V vs Ag/AgCl. The internal or external imidazole coordination to the 3N core resulted in a slight destabilization of the Cu(I) state and stabilization of the Cu(III) state. Taken together these results indicate that A?5-x peptides, which bind Cu(II) ions much more strongly than A?1-x peptides and only slightly weaker than A?4-x peptides could interfere with Cu(II) handling by these peptides, adding to copper dyshomeostasis in Alzheimer brains.

SUBMITTER: Wezynfeld NE 

PROVIDER: S-EPMC7539298 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature