NMR solution structure of rat aβ(1-16): toward understanding the mechanism of rats' resistance to Alzheimer's disease.
In an attempt to reveal the mechanism of rats' resistance to Alzheimer's disease, we determined the structure of the metal-binding domain 1-16 of rat β-amyloid (rat Aβ(1-16)) in solution in the absence and presence of zinc ions. A zinc-induced dimerization of the domain was detected. The zinc coordination site was found to involve residues His-6 and His-14 of both peptide chains. We used experimental restraints obtained from analyses of NMR and isothermal titration calorimetry data to perform structure calculations. The calculations employed an explicit water environment and a simulated annealing molecular-dynamics protocol followed by quantum-mechanical/molecular-mechanical optimization. We found that the C-tails of the two polypeptide chains of the rat Aβ(1-16) dimer are oriented in opposite directions to each other, which hinders the assembly of rat Aβ dimers into oligomeric aggregates. Thus, the differences in the structure of zinc-binding sites of human and rat Aβ(1-16), their ability to form regular cross-monomer bonds, and the orientation of their hydrophobic C-tails could be responsible for the resistance of rats to Alzheimer's disease.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Andrey N
AN
Istrate
Philipp O
PO
Tsvetkov
Alexey B
AB
Mantsyzov
Alexandra A
AA
Kulikova
Sergey A
SA
Kozin
Alexander A
AA
Makarov
Vladimir I
VI
Polshakov
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity; D015032:Zinc / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C433241:amyloid beta-protein (1-16); D015032:Zinc