Zn⁺⁺ Binding Disrupts the Asp²³-Lys²⁸ Salt Bridge without Altering the Hairpin-Shaped Cross-¦Â Structure of A¦Â₄₂ Amyloid Aggregates

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• 作者：Venus  ; Singh Mithu^&dagger ; ; Bidyut Sarkar^&dagger ; ; Debanjan Bhowmik^&dagger ; ; Muralidharan Chandrakesan^&Dagger ; ; Sudipta Maiti^&dagger ; ;   ; ^{maiti@tifr.res.in} ; Perunthiruthy  ; K. Madhu^&dagger ; ;   ; ^{madhu@tifr.res.in}
• 刊名：Biophysical Journal
• 出版年：2011
• 出版时间：7 December 2011
• 年：2011
• 卷：101
• 期：11
• 页码：2825-2832
• 全文大小：526 K

文摘

Observations like high Zn²⁺ concentrations in senile plaques found in the brains of Alzheimer's patients and evidences emphasizing the role of Zn²⁺ in amyloid-¦Â (A¦Â)-induced toxicity have triggered wide interest in understanding the nature of Zn²⁺-A¦Â interaction. In?vivo and in?vitro studies have shown that aggregation kinetics, toxicity, and morphology of A¦Â aggregates are perturbed in the presence of Zn²⁺. Structural studies have revealed that Zn²⁺ has a binding site in the N-terminal region of monomeric A¦Â, but not much is precisely known about the nature of binding of Zn²⁺ with aggregated forms of A¦Â or its effect on the molecular structure of these aggregates. Here, we explore this aspect of the Zn²⁺-A¦Â interaction using one- and two-dimensional ¹³C and ¹⁵N solid-state NMR. We find that Zn²⁺ causes major structural changes in the N-terminal and the loop region connecting the two ¦Â-sheets. It breaks the salt bridge between the side chains of Asp²³ and Lys²⁸ by driving these residues into nonsalt-bridge-forming conformations. However, the cross-¦Â structure of A¦Â₄₂ aggregates remains unperturbed though the fibrillar morphology changes distinctly. We conclude that the salt bridge is not important for defining the characteristic molecular architecture of A¦Â₄₂ but is significant for determining its fibrillar morphology and toxicity.