Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides.
The Zn(II) ion has been linked to Alzheimer's disease (AD) due to its ability to modulate the aggregating properties of the amyloid-β (Aβ) peptide, where Aβ aggregation is a central event in the etiology of the disease. Delineating Zn(II) binding properties to Aβ is thus a prerequisite to better grasp its potential role in AD. Because of (i) the flexibility of the Aβ peptide, (ii) the multiplicity of anchoring sites, and (iii) the silent nature of the Zn(II) ion in most classical spectroscopies, this is a difficult task. To overcome these difficulties, we have investigated the impact of peptide alterations (mutations, N-terminal acetylation) on the Zn(Aβ) X-ray absorption spectroscopy fingerprint and on the Zn(II)-induced modifications of the Aβ peptides' NMR signatures. We propose a tetrahedrally bound Zn(II) ion, in which the coordination sphere is made by two His residues and two carboxylate side chains. Equilibria between equivalent ligands for one Zn(II) binding position have also been observed, the predominant site being made by the side chains of His6, His13 or His14, Glu11, and Asp1 or Glu3 or Asp7, with a slight preference for Asp1.
CNRS, LCC (Laboratoire de Chimie de Coordination) , 205 Route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|Université de Toulouse , UPS, INPT, F-31077 Toulouse Cedex 4, France.
Bruno
B
Alies
CNRS, LCC (Laboratoire de Chimie de Coordination) , 205 Route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|Université de Toulouse , UPS, INPT, F-31077 Toulouse Cedex 4, France.
Amandine
A
Conte-Daban
Université Reims Champagne Ardenne , Institut de Chimie Moléculaire de Reims (ICMR), UMR 7312 CNRS-URCA, Moulin de la Housse, BP 1039, 51687 Reims Cedex 2, France.
Stéphanie
S
Sayen
CNRS, LCC (Laboratoire de Chimie de Coordination) , 205 Route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|Université de Toulouse , UPS, INPT, F-31077 Toulouse Cedex 4, France.|Université de Toulouse , UPS, UMR 152 PHARMA-DEV, Université Toulouse 3, and Institut de Recherche pour le Développement (IRD), UMR 152 PHARMA-DEV, F-31062 Toulouse Cedex 09, France.
Fabrice
F
Collin
Observatoire des Sciences de l'Univers de Grenoble (OSUG) , CNRS UMS 832, 414 Rue de la Piscine, 38400 Saint Martin d'Hères, France.|BM30B/FAME, ESRF, The European Synchrotron , 71 Avenue des Martyrs, 38000 Grenoble, France.
Isabelle
I
Kieffer
Université Reims Champagne Ardenne , Institut de Chimie Moléculaire de Reims (ICMR), UMR 7312 CNRS-URCA, Moulin de la Housse, BP 1039, 51687 Reims Cedex 2, France.
Emmanuel
E
Guillon
CNRS, LCC (Laboratoire de Chimie de Coordination) , 205 Route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|Université de Toulouse , UPS, INPT, F-31077 Toulouse Cedex 4, France.
Peter
P
Faller
CNRS, LCC (Laboratoire de Chimie de Coordination) , 205 Route de Narbonne, BP 44099, F-31077 Toulouse Cedex 4, France.|Université de Toulouse , UPS, INPT, F-31077 Toulouse Cedex 4, France.
Christelle
C
Hureau
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D066244:Proton Magnetic Resonance Spectroscopy; D056928:X-Ray Absorption Spectroscopy; D015032:Zinc / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D006639:Histidine; D015032:Zinc
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