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- Title
Fibrillization of Human Tau Is Accelerated by Exposure to Lead via Interaction with His-330 and His-362.
- Authors
Hai-Li Zhu; Sheng-Rong Meng; Jun-Bao Fan; Jie Chen; Yi Liang
- Abstract
Background: Neurofibrillary tangles, mainly consisted of bundles of filaments formed by the microtubule-associated protein Tau, are a hallmark of Alzheimer disease. Lead is a potent neurotoxin for human being especially for the developing children, and Pb2+ at high concentrations is found in the brains of patients with Alzheimer disease. However, it has not been reported so far whether Pb2+ plays a role in the pathology of Alzheimer disease through interaction with human Tau protein and thereby mediates Tau filament formation. In this study, we have investigated the effect of Pb2+ on fibril formation of recombinant human Tau fragment Tau244-372 and its mutants at physiological pH. Methodology/Principal Findings: As revealed by thioflavin T and 8-anilino-1-naphthalene sulfonic acid fluorescence, the addition of 5-40 mM Pb2+ significantly accelerates the exposure of hydrophobic region and filament formation of wild-type Tau244-372 on the investigated time scale. As evidenced by circular dichroism and Fourier transform infrared spectroscopy, fibrils formed by wild-type Tau244-372 in the presence of 5-40 mM Pb2+ contain more b-sheet structure than the same amount of fibrils formed by the protein in the absence of Pb2+. However, unlike wild-type Tau244-372, the presence of 5- 40 &mgr;M Pb2+ has no obvious effects on fibrillization kinetics of single mutants H330A and H362A and double mutant H330A/ H362A, and fibrils formed by such mutants in the absence and in the presence of Pb2+ contain similar amounts of &bgr;-sheet structure. The results from isothermal titration calorimetry show that one Pb2+ binds to one Tau monomer via interaction with His-330 and His-362, with sub-micromolar affinity. Conclusions/Significance: We demonstrate for the first time that the fibrillization of human Tau protein is accelerated by exposure to lead via interaction with His-330 and His-362. Our results suggest the possible involvement of Pb2+ in the pathogenesis of Alzheimer disease and provide critical insights into the mechanism of lead toxicity.
- Publication
PLoS ONE, 2011, Vol 6, Issue 9, p1
- ISSN
1932-6203
- Publication type
Academic Journal
- DOI
10.1371/journal.pone.0025020