Metal-dependent interactions of metallothionein-3 β-domain with amyloid-β peptide and related physiological implications.

J Inorg Biochem

College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China. Electronic address:

Published: July 2019

AI Article Synopsis

  • Aberrant interactions of metal ions with amyloid-β peptide (Aβ) can worsen Alzheimer's disease by promoting Aβ aggregation and generating reactive oxygen species (ROS).
  • Metallothionein-3 (MT3) is implicated in Alzheimer's progression due to its role in regulating metal balance and scavenging ROS, though its exact mechanisms are not well understood.
  • This study reveals that Zn-βMT3 has a stronger affinity for Aβ compared to Cu-βMT3, highlighting the protective role of Zn-MT3 in preventing copper-induced neurotoxicity in Aβ, which may aid in developing treatments for Alzheimer's disease.

Article Abstract

Aberrant interactions of metal ions with amyloid-β peptide (Aβ) can potentiate Alzheimer's disease (AD) by participating in the aggregation process of Aβ and in the generation of reactive oxygen species (ROS). Metallothionein-3 (MT3), which is aberrantly expressed in AD brains, is believed to play an important role in the AD progression due to its ability of maintaining metal homeostasis and scavenging ROS. However, the related molecular mechanism is not clear. In this work, the metal-dependent interactions of MT3 β-domain (βMT3) with amyloid-β peptide (Aβ) were systematically studied. The results showed that Zn-βMT3 has a higher affinity to Aβ (K: ~0.7 μM) than Cu-βMT3 (K: ~22 μM). In Zn-βMT3, both Pro and Pro face outwards with their five-member rings in parallel, favoring their binding with aromatic residues via CH/π interactions. Two aromatic residues (Phe and Tyr) in Aβ were identified as the specific binding sites for βMT3. Based on these, we posit a characteristic in-situ protection role of Zn-MT3 in inhibiting the Cu-induced Aβ neurotoxicity, in which stable Zn-MT3/Aβ complex forms via the Zn-βMT3/Aβ interaction and effectively prevents the formation of Cu-Aβ in high viscosity physiological fluids. Our results provide the mechanistic pathway and the specific roles of βMT3 in its protective bioactivity against AD progression, which means significant for elucidating the function of MT3 in AD neuropathology and for designing a MT3-related therapeutic strategy for AD.

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Source
http://dx.doi.org/10.1016/j.jinorgbio.2019.110693DOI Listing

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