pH-Dependent Cu(II) Coordination to Amyloid-β Peptide: Impact of Sequence Alterations, Including the H6R and D7N Familial Mutations.

Abstract

Copper ions have been proposed to intervene in deleterious processes linked to the development of Alzheimer’s disease (AD). As a direct consequence, delineating how Cu(II) can be bound to amyloid-β (Aβ) peptide, the amyloidogenic peptide encountered in AD, is of paramount importance. Two different forms of [Cu^II(Aβ)] complexes are present near physiological pH, usually noted components <b>I</b> and <b>II</b>, the nature of which is still widely debated in the literature, especially for <b>II</b>. In the present report, the phenomenological pH-dependent study of Cu(II) coordination to Aβ and to ten mutants by EPR, CD, and NMR techniques is described. Although only indirect insights can be obtained from the study of Cu(II) binding to mutated peptides, they reveal very useful for better defining Cu(II) coordination sites in the native Aβ peptide. Four components were identified between pH 6 and 12, namely, components <b>I</b>, <b>II</b>, <b>III</b> and <b>IV</b>, in which the predominant Cu(II) equatorial sites are {−NH₂, CO (Asp1–Ala2), N_im (His6), N_im (His13 or His14)}, {−NH₂, N^– (Asp1–Ala2), CO (Ala2–Glu3), N_im}, {−NH₂, N^– (Asp1–Ala2), N^– (Ala2–Glu3), N_im} and {−NH₂, N^– (Asp1–Ala2), N^– (Ala2–Glu3), N^– (Glu3–Phe4)}, respectively, in line with classical pH-induced deprotonation of the peptide backbone encountered in Cu(II) peptidic complexes formation. The structure proposed for component <b>II</b> is discussed with respect to another coordination model reported in the literature, that is, {CO (Ala2–Glu3), 3 N_im}. Cu(II) binding to the H6R-Aβ and D7N-Aβ peptides, where the familial H6R and D7N mutations have been linked to early onset of AD, has also been investigated. In case of the H6R mutation, some different structural features (compared to those encountered in the native [Cu^II(Aβ)] species) have been evidenced and are anticipated to be important for the aggregating properties of the H6R-Aβ peptide in presence of Cu(II)