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Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments

by 1 and 1,2,3,*
1
Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
2
Department of Mathematical and Life Sciences, Graduate School of the Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
3
Research Center for the Mathematics on Chromatin Live Dynamics (RcMcD), Hiroshima University, 1-3-1, Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(11), 3920; https://doi.org/10.3390/ijms21113920
Received: 1 May 2020 / Revised: 28 May 2020 / Accepted: 29 May 2020 / Published: 30 May 2020
(This article belongs to the Special Issue Structural Biology of Proteins and Peptides)
Tau forms intracellular insoluble aggregates as a neuropathological hallmark of Alzheimer’s disease. Tau is largely unstructured, which complicates the characterization of the tau aggregation process. Recent studies have demonstrated that tau samples two distinct conformational ensembles, each of which contains the soluble and aggregation-prone states of tau. A shift to populate the aggregation-prone ensemble may promote tau fibrillization. However, the mechanism of this ensemble transition remains elusive. In this study, we explored the conformational dynamics of a tau fragment by using paramagnetic relaxation enhancement (PRE) and interference (PRI) NMR experiments. The PRE correlation map showed that tau is composed of segments consisting of residues in correlated motions. Intriguingly, residues forming the β-structures in the heparin-induced tau filament coincide with residues in these segments, suggesting that each segment behaves as a structural unit in fibrillization. PRI data demonstrated that the P301L mutation exclusively alters the transiently formed tau structures by changing the short- and long-range correlated motions among residues. The transient conformations of P301L tau expose the amyloid motif PHF6 to promote tau self-aggregation. We propose the correlated motions among residues within tau determine the population sizes of the conformational ensembles, and perturbing the correlated motions populates the aggregation-prone form. View Full-Text
Keywords: tau protein; intrinsically disordered protein; NMR; paramagnetic relaxation enhancement tau protein; intrinsically disordered protein; NMR; paramagnetic relaxation enhancement
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MDPI and ACS Style

Kawasaki, R.; Tate, S.-i. Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments. Int. J. Mol. Sci. 2020, 21, 3920. https://doi.org/10.3390/ijms21113920

AMA Style

Kawasaki R, Tate S-i. Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments. International Journal of Molecular Sciences. 2020; 21(11):3920. https://doi.org/10.3390/ijms21113920

Chicago/Turabian Style

Kawasaki, Ryosuke, and Shin-ichi Tate. 2020. "Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments" International Journal of Molecular Sciences 21, no. 11: 3920. https://doi.org/10.3390/ijms21113920

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