Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments
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 wh...
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doaj-111f9c1db3fe42f7a8128a319baf5b302020-11-25T02:15:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-01213920392010.3390/ijms21113920Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR ExperimentsRyosuke Kawasaki0Shin-ichi Tate1Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, JapanDepartment of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, JapanTau 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.https://www.mdpi.com/1422-0067/21/11/3920tau proteinintrinsically disordered proteinNMRparamagnetic relaxation enhancement |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ryosuke Kawasaki Shin-ichi Tate |
spellingShingle |
Ryosuke Kawasaki Shin-ichi Tate 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 tau protein intrinsically disordered protein NMR paramagnetic relaxation enhancement |
author_facet |
Ryosuke Kawasaki Shin-ichi Tate |
author_sort |
Ryosuke Kawasaki |
title |
Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments |
title_short |
Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments |
title_full |
Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments |
title_fullStr |
Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments |
title_full_unstemmed |
Impact of the Hereditary P301L Mutation on the Correlated Conformational Dynamics of Human Tau Protein Revealed by the Paramagnetic Relaxation Enhancement NMR Experiments |
title_sort |
impact of the hereditary p301l mutation on the correlated conformational dynamics of human tau protein revealed by the paramagnetic relaxation enhancement nmr experiments |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-05-01 |
description |
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. |
topic |
tau protein intrinsically disordered protein NMR paramagnetic relaxation enhancement |
url |
https://www.mdpi.com/1422-0067/21/11/3920 |
work_keys_str_mv |
AT ryosukekawasaki impactofthehereditaryp301lmutationonthecorrelatedconformationaldynamicsofhumantauproteinrevealedbytheparamagneticrelaxationenhancementnmrexperiments AT shinichitate impactofthehereditaryp301lmutationonthecorrelatedconformationaldynamicsofhumantauproteinrevealedbytheparamagneticrelaxationenhancementnmrexperiments |
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1724894936206147584 |