ABSTRACT
Conformational changes of Aß peptide result in its transformation from native monomeric state to the toxic soluble dimers, oligomers and insoluble aggregates that are hallmarks of Alzheimer's disease (AD). Interactions of zinc ions with Aß are mediated by the N-terminal Aß(1-16) domain and appear to play a key role in AD progression. There is a range of results indicating that these interactions trigger the Aß plaque formation. We have determined structure and functional characteristics of the metal binding domains derived from several Aß variants and found that their zinc-induced oligomerization is governed by conformational changes in the minimal zinc binding site 6HDSGYEVHH14. The residue H6 and segment 11EVHH14, which are part of this site are crucial for formation of the two zinc-mediated interaction interfaces in Aß. These structural determinants can be considered as promising targets for rational design of the AD-modifying drugs aimed at blocking pathological Aß aggregation.
Subject(s)
Amyloid beta-Peptides/chemistry , Histidine/chemistry , Peptide Fragments/chemistry , Zinc/chemistry , Amino Acid Sequence , Amino Acid Substitution , Amyloid beta-Peptides/chemical synthesis , Binding Sites , Humans , Molecular Dynamics Simulation , Nuclear Magnetic Resonance, Biomolecular , Peptide Fragments/chemical synthesis , Protein Aggregates , Protein Binding , Protein Domains , Protein Multimerization , SolutionsABSTRACT
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 ß-amyloid (rat Aß(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 Aß(1-16) dimer are oriented in opposite directions to each other, which hinders the assembly of rat Aß dimers into oligomeric aggregates. Thus, the differences in the structure of zinc-binding sites of human and rat Aß(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.