文章基本信息

标题：Copper mediated amyloid-β binding to Transthyretin
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作者：Lidia Ciccone ; Carole Fruchart-Gaillard ; Gilles Mourier 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2018
卷号：8
期号：1
页码：13744
DOI：10.1038/s41598-018-31808-5
语种：English
出版社：Springer Nature
摘要：Transthyretin (TTR), a homotetrameric protein that transports thyroxine and retinol both in plasma and in cerebrospinal (CSF) fluid provides a natural protective response against Alzheimer’s disease (AD), modulates amyloid- β (A β ) deposition by direct interaction and co-localizes with A β in plaques. TTR levels are lower in the CSF of AD patients. Zn²⁺, Mn²⁺ and Fe²⁺ transform TTR into a protease able to cleave A β . To explain these activities, monomer dissociation or conformational changes have been suggested. Here, we report that when TTR crystals are exposed to copper or iron salts, the tetramer undergoes a significant conformational change that alters the dimer-dimer interface and rearranges residues implicated in TTR’s ability to neutralize A β . We also describe the conformational changes in TTR upon the binding of the various metal ions. Furthermore, using bio-layer interferometry (BLI) with immobilized A β (1–28), we observe the binding of TTR only in the presence of copper. Such Cu²⁺-dependent binding suggests a recognition mechanism whereby Cu²⁺ modulates both the TTR conformation, induces a complementary A β structure and may participate in the interaction. Cu²⁺-soaked TTR crystals show a conformation different from that induced by Fe²⁺, and intriguingly, TTR crystals grown in presence of A β (1–28) show different positions for the copper sites from those grown its absence.