NMR Studies of Tau Protein in Tauopathies

Škrabana, Rostislav; Gašparik, Norbert; Hritz, Jozef; Jaudzems, Kristaps

doi:10.3389/fmolb.2021.761227

Cited by 12 publications

(8 citation statements)

References 132 publications

(213 reference statements)

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“…The structure of a full-length tau (hTau40; 441 residues) monomer remains to be solved experimentally, due mainly to its polymorphic nature. Much of the available knowledge is based on Nuclear Magnetic Resonance (NMR) spectra of its individual fragments, and complete spectral assignment has been achieved, denoting a predominantly random coil conformation of the isolated protein, with secondary structural propensities in different regions [49]. The two hexapeptide motifs within tau, designated PHF6 * and PHF6, have tendency to form β-sheet structures [50,51].…”

Section: Model Buildingmentioning

confidence: 99%

Modelling peptide self-assembly within a partially disordered tau filament

et al. 2022

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Peptide self-assemblies are a natural template for designing bio-inspired functional materials given the extensive characterisation of neurodegenerative and non-disease biological amyloid protein assemblies and advances in rational, modelling-led materials design. These bioinspired materials employ design rules obtained from known aggregation-prone peptides or de novo screening for sequences most amenable to self-assemble functional nanostructures. Here, we exploit the hybrid nature of a complex peptide with both ordered crystalline and intrinsically disordered regions, namely, the microtubule-binding domain (MBD) of tau protein, to probe the physical driving forces for self-assembly at the molecular level. We model the peptide in its native and mutated states to identify the supramolecular packing driving stabilisation at the prefibrillar level. We use extensive atomic-resolution molecular dynamics computer simulations, contact maps, hydrogen-bond networks and free energy calculations to model the tau MBD and its two known familial mutants, the P301L and K280Δ, along with a control double mutant, P301L+ K280Δ as a first step towards understanding their effects on oligomer stability in fibrillar fold. Our results indicate that the mutations destabilise supramolecular packing in the pro-fibrillar hexamer by breaking contacts in the ordered domain of tau MBD, which helps explain mutation-induced toxicity levels as the more stable wild-type peptide assemblies may be less prone to crumbling, producing fewer toxic small oligomeric seeds. Our most important finding is that tau familial mutations causing frontotemporal dementia may show distinct morphologies delineating different stages of self-assembly. The models show that the P301L mutant is more pro-nucleating with low tendency for assembly polymerisation, whereas K280 is more pro-elongating with potential for protofibrillar growth. Our data provides a predictive mechanistic model for distinct peptide self-assembly features depending on the location and nature of single missense mutations on the partially disordered pathogenic MBD, which may explain the prevalence of polymorphic filamentous tau strains observed experimentally.

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Section: Model Buildingmentioning

confidence: 99%

Modelling peptide self-assembly within a partially disordered tau filament

et al. 2022

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“…In our current study, we inspect the residue-specific hotspots vital for amyloidogenesis of R3 repeat and the influence of G326E mutation that disfavors fibril formation with NMR experiments. Solution NMR , has been the powerhouse experimental tool for studying monomeric properties of IDPs, particularly the Tau protein, as it offers insights into the residue-specific perturbations. ,,,,, For our study, we employed two R1R3 constructs: the R1R3 wild-type (WT) and the R1R3-G326E mutant (EE) (Figure C). The conformational changes occurring on G326E mutation are probed through average 1 H– 15 N chemical shift differences and 13 C secondary chemical shift differences.…”

Section: Introductionmentioning

confidence: 99%

“…In vitro studies have primarily focused on understanding the conformational properties of the monomeric Tau, 9,11,16,26 and the effect of cofactors, 27,28 metals, 29,30 pathological mutations, 31 post-translational modifications, 12,32,33 and tubulin/ MT binding 4,34,35 to name a few. Biophysical techniques employed for these studies encompass a range of methods, such as solution, solid-state NMR, 36 EPR, 37 fluorescence experiments, 38,39 cryo-electron microscopy, 40 and molecular dynamics. 41,42 on binding to lipids, 43 Tau is disordered in its MT-bound state.…”

Section: ■ Introductionmentioning

confidence: 99%

Role of G326 in Determining the Aggregation Propensity of R3 Tau Repeat: Insights from Studies on R1R3 Tau Construct

Sahayaraj,

Abdul Vahid,

Dhara

et al. 2024

J. Phys. Chem. B

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The Microtubule-binding repeat region (MTBR) of Tau has been studied extensively due to its pathological implications in neurodegenerative diseases like Alzheimer's disease. The pathological property of MTBR is mainly due to the R3 repeat's high propensity for self-aggregation, highlighting the critical molecular grammar of the repeat. Utilizing the R1R3 construct (WT) and its G326E mutant (EE), we determine the distinct characteristics of various peptide segments that modulate the aggregation propensity of the R3 repeat using NMR spectroscopy. Through time-dependent experiments, we have identified 317 KVTSKCGS 324 in R3 repeat as the aggregation initiating motif (AIM) due to its role at the initial stages of aggregation. The G326E mutation induces changes in conformation and dynamics at the AIM, thereby effectively abrogating the aggregation propensity of the R1R3 construct. We further corroborate our findings through MD simulations and propose that AIM is a robust site of interest for tauopathy drug design.

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“…The isoforms differ by the number of N-terminal inserts (0N, 1N or 2N) and C-terminal repeats (3R or 4R isoforms) [8]. An enormous amount of work utilizing various biophysical techniques has been done to investigate the filamentous tau structures and identify the parts of the protein which are incorporated into the rigid cores of the filaments [9,10]. Typically, the disease-associated tau filament cores do not exceed one-quarter of the protein sequence.…”

Section: Introductionmentioning

confidence: 99%

dGAE(297-391) tau fragment promotes formation of CTE-like full-length tau filaments

Lends

Kucinskas²,

Bula

et al. 2023

Preprint

Self Cite

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The microtubule associated protein tau forms disease-specific filamentous aggregates in several different neurodegenerative diseases. In order to understand how tau undergoes misfolding into a specific filament type and to be able to control this process for drug development purposes, it is crucial to study in vitro tau aggregation methods and investigate the structures of the obtained filaments at atomic level. Here, we used the tau fragment dGAE(297-391), which aggregates spontaneously, to seed formation of full-length tau filaments. The structures of dGAE and full-length tau filaments were investigated by solid-state MAS NMR showing that dGAE allows propagating a chronic traumatic encephalopathy (CTE)-like fold to full-length tau. This work demonstrates that in vitro preparation of disease-specific types of full-length tau filaments is feasible.

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NMR Studies of Tau Protein in Tauopathies

Cited by 12 publications

References 132 publications

Modelling peptide self-assembly within a partially disordered tau filament

Modelling peptide self-assembly within a partially disordered tau filament

Role of G326 in Determining the Aggregation Propensity of R3 Tau Repeat: Insights from Studies on R1R3 Tau Construct

dGAE(297-391) tau fragment promotes formation of CTE-like full-length tau filaments

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