Mercury(II) promotes the in vitro aggregation of tau fragment corresponding to the second repeat of microtubule-binding domain: Coordination and conformational transition.
The loss of metal homeostasis and the toxic effect of metal ion are important events in neurodegenerative and age-related diseases, such as Alzheimer's disease (AD). For the first time, we investigated the impacts of mercury(II) ions on the folding and aggregation of Alzheimer's tau fragment R2 (residues 275-305: VQIIN KKLDL SNVQS KCGSK DNIKH VPGGGS), corresponding to the second repeat unit of the microtubule-binding domain, which was believed to be pivotal to the biochemical properties of full tau protein. By ThS fluorescence assay and electron microscopy, we found that mercury(II) dramatically promoted heparin-induced aggregation of R2 at an optimum molar ratio of 1: 2 (metal: protein), and the resulting R2 filaments became smaller. Isothermal titration calorimetry (ITC) experiment revealed that the strong coordination of mercury(II) with R2 was an enthalpy-controlled, entropy-decreased thermodynamic process. The exceptionally large magnitude of heat release (ΔH₁ = -34.8 Kcal mol⁻¹) suggested that the most possible coordinating site on the R2 peptide chain was the thiol group of cysteine residue (Cys291), and this was further confirmed by a control experiment using Cys291 mutated R2. Circular dichroism spectrum demonstrated that this peptide underwent a significant conformational change from random coil to β-turn structure upon its binding to mercury(II) ion. This study was undertaken to better understand the mechanism of tau aggregation, and evaluate the possible role of mercury(II) in the pathogenesis of AD.
Yang
Dan-Jing
DJ
Department of Chemistry, Tongji University, Shanghai 200092, China.
Shi
Shuo
S
Zheng
Leng-Feng
LF
Yao
Tian-Ming
TM
Ji
Liang-Nian
LN
D000465:Algorithms; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002151:Calorimetry / Q000379:methods; D002942:Circular Dichroism; D006801:Humans; D008628:Mercury / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D010446:Peptide Fragments; D016875:tau Proteins; D008628:Mercury