tailieunhanh - Báo cáo khoa học: High-resolution NMR studies of the zinc-binding site of the Alzheimer’s amyloid b-peptide

Metal binding to the amyloidb-peptide is suggested to be involved in the pathogenesis of Alzheimer’s disease. We used high-resolution NMR to study zinc binding to amyloid b-peptide 1–40 at physiologic pH. Metal binding induces a structural change in the peptide, which is in chemical exchange on an intermediate rate, between the apo-form and the holo-form, with respect to the NMR timescale. | ễFEBS Journal High-resolution NMR studies of the zinc-binding site of the Alzheimer s amyloid b-peptide Jens Danielsson1 Roberta Pierattelli2 Lucia Banci2 and Astrid Graslund1 1 Department of Biochemistry and Biophysics Stockholm University Sweden 2 Department of Chemistry and Magnetic Resonance Center University di Firenze Sesto Fiorentino Italy Keywords aggregation Alzheimer amyloid b-peptide copper binding NMR zinc binding Correspondence A. Graslund Department of Biochemistry and Biophysics Stockholm University S-106 91 Stockholm Sweden Fax 46 8 155597 Tel 46 8 162450 E-mail astrid@ Received 22 June 2006 revised 20 October 2006 accepted 27 October 2006 doi Metal binding to the amyloid b-peptide is suggested to be involved in the pathogenesis of Alzheimer s disease. We used high-resolution NMR to study zinc binding to amyloid b-peptide 1-40 at physiologic pH. Metal binding induces a structural change in the peptide which is in chemical exchange on an intermediate rate between the apo-form and the holo-form with respect to the NMR timescale. This causes loss of NMR signals in the resonances affected by the binding. Heteronuclear correlation experiments 15N-relaxation and amide proton exchange experiments on amyloid b-pep-tide 1-40 revealed that zinc binding involves the three histidines residues 6 13 and 14 and the N-terminus similar to a previously proposed copper-binding site Syme CD Nadal RC Rigby SE Viles JH 2004 J Biol Chem 279 18169-18177 . Fluorescence experiments show that zinc shares a common binding site with copper and that the metals have similar affinities for amyloid b-peptide. The dissociation constant Kd of zinc for the fragment amyloid b-peptide 1-28 was measured by fluorescence using competitive binding studies and that for amyloid b-peptide 1-40 was measured by NMR. Both methods gave Kd values in the micromolar range at pH and 286 K. Zinc also has a second weaker binding site involving residues .

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