ИСТИНА

A key factor of Alzheimer’s disease progression is abnormal aggregation of beta-amyloid (Aβ) peptide. This process is started by interaction of Aβ N-terminal domain (“metal binding domain”) with zinc ion, which leads to conformational changes of Aβ molecules. Several mutations within Aβ metal binding domain dramatically increase Alzheimer’s disease risk. In the present study, we used high resolution NMR spectroscopy to reveal the structural determinants of zinc-induced Aβ oligomerization. On the first stage, the dimeric Aβ-zinc-Aβ complexes are formed, where zinc ion is coordinated by E11 and H14 residues of Aβ molecules. We have determined a high resolution spatial structure of such complexes for the Aβ(1-16)-H6R, where histidine-6 is substituted by arginine. This structure was calculated using NOESY restrains and refined by QM/MM calculations. Further oligomerization of dimeric complexes requires a second zinc-coordination site. It was shown to be formed by H6 and H13 residues. The substitution of one of these histidines to arginine prevents Aβ oligomerization. On the other hand, several Aβ mutants show much higher propensity to oligomreization due to increased conformational freedom of H6 residue. The obtained results clarify molecular mechanism of the zinc-induced Aβ oligomerization and provide structural basis for rational design of drugs aimed to block pathological beta-amyloid peptide aggregation.