title: 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 I and II, the nature of which is still widely debated in the literature, especially for II. 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 I, II, III and IV, in which the predominant Cu(II) equatorial sites are {-NH(2), CO (Asp1-Ala2), N(im) (His6), N(im) (His13 or His14)}, {-NH(2), N(-) (Asp1-Ala2), CO (Ala2-Glu3), N(im)}, {-NH(2), N(-) (Asp1-Ala2), N(-) (Ala2-Glu3), N(im)} and {-NH(2), 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 II 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).
authors: CNRS, LCC (Laboratoire de Chimie de Coordination), 205, route de Narbonne, F-31077 Toulouse, France.
authors: Bruno
authors: B
authors: Alies
authors: Hélène
authors: H
authors: Eury
authors: Christian
authors: C
authors: Bijani
authors: Lionel
authors: L
authors: Rechignat
authors: Peter
authors: P
authors: Faller
authors: Christelle
authors: C
authors: Hureau
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017354:Point Mutation; D011485:Protein Binding; D012996:Solutions
chemical_list: D000596:Amino Acids; D016229:Amyloid beta-Peptides; D012996:Solutions; D003300:Copper