Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations

Dong, Xiaowei; Qi, Ruxi; Qiao, Qin; Li, Xuhua; Li, Fangying; Wan, Jiaqian; Zhang, Qingwen; Wei, Guanghong

doi:10.1039/d1cp02651h

Cited by 18 publications

(23 citation statements)

References 81 publications

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“…However, the FUS 37–97 dimer presents higher β structures (∼14.4%) and lower helices (∼3.3%) than the FUS 37–97 monomer (∼9.4% β structures and ∼5.7% helices), and peptides are more extended with larger single-chain R g values (∼1.2 nm) in the two dimer systems than those in monomer systems (∼1.1 nm) (Table and Figure S10a). Similar results are reported in previous REMD simulation studies for other amyloid peptide fragments (such as tau 306–336 and hIAPP 11–25 ) showing that peptides in oligomers are more extended and possess higher β-sheet contents than monomers. ,, In comparison with the FUS 37–97 dimer, the pFUS 37–97 dimer has an eminently decreased β probability and a drastically increased helix probability (Figure a, Table , Figure S10b,c). In the FUS 37–97 dimer system, β structures are predominantly distributed in the region encompassing residues 52–61 and 63–69 (Figure b), which are mostly located in the amyloid core region (residues 52–67).…”

Section: Resultssupporting

confidence: 87%

“…Similar results are reported in previous REMD simulation studies for other amyloid peptide fragments (such as tau 306−336 and hIAPP 11−25 ) showing that peptides in oligomers are more extended and possess higher β-sheet contents than monomers. 65,72,73 In comparison with the FUS 37−97 dimer, the pFUS 37−97 dimer has an eminently decreased β probability and a drastically increased helix probability (Figure 2a, Table 1, Figure S10b,c). In the FUS 37−97 dimer system, β structures are predominantly distributed in the region encompassing residues 52−61 and 63−69 (Figure 2b), which are mostly located in the amyloid core region (residues 52−67).…”

Section: ■ Models and Methodsmentioning

confidence: 99%

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Insights into the Atomistic Mechanisms of Phosphorylation in Disrupting Liquid–Liquid Phase Separation and Aggregation of the FUS Low-Complexity Domain

Lao

Dong

Liu

et al. 2022

J. Chem. Inf. Model.

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Fused in sarcoma (FUS), a nuclear RNA binding protein, can not only undergo liquid−liquid phase separation (LLPS) to form dynamic biomolecular condensates but also aggregate into solid amyloid fibrils which are associated with the pathology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration diseases. Phosphorylation in the FUS lowcomplexity domain (FUS-LC) inhibits FUS LLPS and aggregation. However, it remains largely elusive what are the underlying atomistic mechanisms of this inhibitory effect and whether phosphorylation can disrupt preformed FUS fibrils, reversing the FUS gel/solid phase toward the liquid phase. Herein, we systematically investigate the impacts of phosphorylation on the conformational ensemble of the FUS 37−97 monomer and dimer and the structure of the FUS 37−97 fibril by performing extensive all-atom molecular dynamics simulations. Our simulations reveal three key findings: (1) phosphorylation shifts the conformations of FUS 37−97 from the β-rich, fibril-competent state toward a helix-rich, fibril-incompetent state; (2) phosphorylation significantly weakens protein−protein interactions and enhances protein−water interactions, which disfavor FUS-LC LLPS as well as aggregation and facilitate the dissolution of the preformed FUS-LC fibril; and (3) the FUS 37−97 peptide displays a high β-strand probability in the region spanning residues 52−67, and phosphorylation at S54 and S61 residues located in this region is crucial for the disruption of LLPS and aggregation of FUS-LC. This study may pave the way for ameliorating phase-separation-related pathologies via site-specific phosphorylation.

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Section: Resultssupporting

confidence: 87%

Section: ■ Models and Methodsmentioning

confidence: 99%

Insights into the Atomistic Mechanisms of Phosphorylation in Disrupting Liquid–Liquid Phase Separation and Aggregation of the FUS Low-Complexity Domain

Lao

Dong

Liu

et al. 2022

J. Chem. Inf. Model.

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“…Moreover, endopeptidase cleavage causes in situ generation of R3 fragments in the human brain . Recent studies reported that R3 has a much higher aggregation propensity than R2. , The residues V306–F378 are incorporated in the core of the Tau filaments isolated from AD patients and is involved in interchain β-sheet formation of R3 domain . Furthermore, the PHF6 fragment (V306–K311) forms the first β-strand of the filament core, which is revealed in a recent cryo-EM study .…”

Section: Introductionmentioning

confidence: 92%

“…7,33 The residues V306−F378 are incorporated in the core of the Tau filaments isolated from AD patients and is involved in interchain β-sheet formation of R3 domain. 34 Furthermore, the PHF6 fragment (V306−K311) forms the first β-strand of the filament core, which is revealed in a recent cryo-EM study. 12 This amyloid motif enhances amyloid formation in vitro 35 and drives pathology in vivo 36 by mediating the conversion between soluble and insoluble states.…”

Section: Introductionmentioning

confidence: 93%

Deciphering the Role of ATP on PHF6 Aggregation

2022

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The aggregation of Tau protein, which are involved in Alzheimer’s disease, are associated with the self-assembly of the hexapeptide sequence, paired helical filament 6 (PHF6) from repeat 3 of Tau. In order to treat Alzheimer’s disease and other such tauopathies, one of the therapeutic strategies is to inhibit aggregation of Tau and its nucleating segments. Therefore, we have studied the effect of adenosine triphosphate (ATP) on the aggregation of PHF6. ATP has, interestingly, demonstrated its ability to inhibit and dissolve protein aggregates. Using classical molecular dynamics simulations, we observed that the hydrophobic core of PHF6 segment displays extended β-sheet conformation, which stabilizes PHF6 aggregates. However, the distribution of ATP around the vicinity of the peptides enables PHF6 to remain discrete and attain random coil conformers. The interpeptide interactions are substituted by PHF6–ATP interactions through hydrogen bonding and hydrophobic interactions (including π–π stacking). Furthermore, the adenosine moiety of ATP contributes more than the triphosphate chain toward PHF6–ATP interaction. Ultimately, this work establishes the inhibitory activity of ATP against Tau aggregation; hence, the therapeutic effect of ATP should be explored further in regard to the effective treatment of Alzheimer’s disease.

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“…Molecular dynamics (MD) simulations have been widely used to investigate the effects of some factors, such as mutations − and small molecules, − on the monomeric conformations and protofibril/fibril structural stability of Aβ/Tau/α-Synuclein proteins. Recently, computational investigations are emerging to explore the influence of mutations on the structural properties and aggregation dynamics of fragments of heterogeneous nuclear ribonucleoproteins TDP-43 and FUS. ,,− For example, Newell et al investigated the impact of a phosphomimetic mutation S375E on a TDP-43 371–376 protofibrillar hexamer and reported that the phosphorylation of S375 disrupted intermolecular interactions and the protofibril structure .…”

Section: Introductionmentioning

confidence: 99%

Atomistic Insights into A315E Mutation-Enhanced Pathogenicity of TDP-43 Core Fibrils

Chen

Liu

et al. 2022

ACS Chem. Neurosci.

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The aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) into fibrillary deposits is implicated in amyotrophic lateral sclerosis (ALS), and some hereditary mutations localized in the low complexity domain (LCD) facilitate the formation of pathogenic TDP-43 fibrils. A recent cryo-EM study reported the atomic-level structures of the A315E TDP-43 LCD (residues 288–319, TDP-43288–319) core fibril in which the protofilaments have R-shaped structures and hypothesized that A315E U-shaped protofilaments can readily convert to R-shaped protofilaments compared to the wild-type (WT) ones. There are no atomic structures of WT protofilaments available yet. Herein, we performed extensive all-atom explicit-solvent molecular dynamics simulations on A315E and WT protofilaments starting from both the cryo-EM-determined R-shaped and our constructed U-shaped structures. Our simulations show that WT protofilaments also adopt the R-shaped structures but are less stable than their A315E counterparts. Except for R293-E315 salt bridges, N312-F316 hydrophobic interactions and F316–F316 π–π stacking interactions are also crucial for the stabilization of the neck region of the R-shaped A315E protofilaments. The loss of R293-E315 salt bridges and the weakened interactions of N312-F316 and F316–F316 result in the reduced stability of the R-shaped WT protofilaments. Simulations starting from U-shaped folds reveal that A315E protofilaments can spontaneously convert to the cryo-EM-derived R-shaped protofilaments, whereas WT protofilaments convert to R-shape-like structures with remodeled neck regions. The R-shape-like WT protofilaments could act as intermediate states slowing down the U-to-R transition. This study reveals that A315E mutation can not only enhance the structural stability of the R-shaped TDP-43288–319 protofilaments but also promote the U-to-R transition, which provides atomistic insights into the A315E mutation-enhanced TDP-43 pathogenicity in ALS.

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Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations

Abstract: Abnormal aggregation of proteins into pathological amyloid fibrils are implicated in a wide range of devastating human neurodegenerative diseases. Intracellular fibrillary inclusions formed by Tau protein are characterized as the...

Cited by 18 publications

References 81 publications

Insights into the Atomistic Mechanisms of Phosphorylation in Disrupting Liquid–Liquid Phase Separation and Aggregation of the FUS Low-Complexity Domain

Insights into the Atomistic Mechanisms of Phosphorylation in Disrupting Liquid–Liquid Phase Separation and Aggregation of the FUS Low-Complexity Domain

Deciphering the Role of ATP on PHF6 Aggregation

Atomistic Insights into A315E Mutation-Enhanced Pathogenicity of TDP-43 Core Fibrils

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