Journal
BIOPHYSICAL JOURNAL
Volume 102, Issue 1, Pages 136-143Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2011.11.4006
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Funding
- Russian Academy of Sciences
- Russian Foundation for Basic Research [11-04-01367-a]
- International Center for Genetic Engineering and Biotechnology [CRP/RUS08-02]
- Russian Federal Program [11.519.11.2008]
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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 beta-amyloid (rat A beta(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 A beta(1-16) dimer are oriented in opposite directions to each other, which hinders the assembly of rat A beta dimers into oligomeric aggregates. Thus, the differences in the structure of zinc-binding sites of human and rat A beta(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.
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