CH–π interaction in VQIVYK sequence elucidated by NMR spectroscopy is essential for PHF formation of tau

Sogawa, Koushirou; Minoura, Katsuhiko; In, Yasuko; Ishida, Toshimasa; Taniguchi, Tohru; Tomoo, Koji

doi:10.1002/bip.22489

Cited by 19 publications

(28 citation statements)

References 29 publications

(39 reference statements)

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“…Changes in aromatic amino acid environment during aggregation may be due to CH-π interactions or π-π stacking. [53][54][55] Importantly, the PCA scores plot and loadings for data on dried samples (figures 3C and D respectively) show a very similar pattern as for BSA species in solution and only small frequency shifts are observed in the Amide I, Amide III and skeletal regions, as well as for tyrosine and phenylalanine (listed in supplementary table 2). Together, this suggests that despite the increase in nonregular structure determined by Amide I deconvolution, aggregation species can still be distinguished by the same spectral features irrespective of whether the spectra are measured in wet or dry conditions.…”

Section: Bovine Serum Albumin (Bsa)mentioning

confidence: 65%

Conformational Evolution of Molecular Signatures during Amyloidogenic Protein Aggregation

Devitt

Rice

Crisford

et al. 2019

ACS Chem. Neurosci.

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Aggregation is a pathological hallmark of proteinopathies such as Alzheimer's disease and results in the deposition of β-sheet-rich amyloidogenic protein aggregates. Such proteinopathies can be classified by the identity of one or more aggregated protein, with recent evidence also suggesting that distinct molecular conformers (strains) of the same protein can be observed in different diseases, as well is in sub-types of the same disease. Therefore, methods for the quantification of pathological changes in protein conformation are central to understanding and treating proteinopathies. In this work the evolution of Raman spectroscopic molecular signatures of three conformationally distinct proteins, Bovine Serum Albumin (α-helical-rich), β2-microglobulin (β-sheetrich) and tau (natively disordered), was assessed during aggregation into oligomers and fibrils. The morphological evolution was tracked using Atomic Force Microscopy and corresponding conformational changes were assessed by their Raman signatures acquired in both wet and dried conditions. A deconvolution model was developed which allowed us to quantify the conformation of the non-regular protein tau, as well as for the oligomeric and fibrillar species of each of the proteins. Principle component analysis of the fingerprint region allowed further identification of the distinguishing spectral features and unsupervised distinction. While an increase in β-sheet is seen on aggregation, crucially, however, each protein also retains a significant proportion of its native monomeric structure after aggregation. Thus, spectral analysis of each aggregated species, oligomeric, as well as fibrillar, for each protein resulted in a unique and quantitative 'conformational fingerprint'. This approach allowed us to provide the first differential detection of both oligomers and fibrils of the three different amyloidogenic proteins, including tau, whose aggregates have never before been interrogated using spontaneous Raman spectroscopy. Quantitative 'conformational fingerprinting' by Raman spectroscopy thus demonstrates its huge potential and utility in understanding proteinopathic disease mechanisms and for providing strain-specific early diagnostic markers and targets for disease-modifying therapies.

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Section: Bovine Serum Albumin (Bsa)mentioning

confidence: 65%

Conformational Evolution of Molecular Signatures during Amyloidogenic Protein Aggregation

Devitt

Rice

Crisford

et al. 2019

ACS Chem. Neurosci.

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“…Interestingly, despite the prominent position of Tyr-310 within the aggregation-prone hexapeptide PHF6 (amino acids 306 -311), only a handful of studies have specifically investigated the roles of this residue in regulating Tau structure, aggregation, and toxicity. Importantly, none of the previous studies (30,(35)(36)(37)(38)(39)(40)(41)(42) specifically investigated the effects of Tyr-310 phosphorylation in the context of the full-length Tau protein, relying instead on the short PHF6-containing peptides, featuring PHF6-derived sequences as short as three amino acids (43). Santa-Maria et al (44) showed that phosphorylation of Tyr-310 abolished the aggregation of the PHF6 fragment (amino acids 306 -311) in vitro.…”

mentioning

confidence: 99%

Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau

Ait-Bouziad

Chiki

Limorenko

et al. 2020

Journal of Biological Chemistry

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The microtubule-associated protein Tau is implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Increasing evidence suggests that post-translational modifications play critical roles in regulating Tau's normal functions and its pathogenic properties in tauopathies. Very little is known about how phosphorylation of tyrosine residues influences the structure, aggregation, and microtubule- and lipid-binding properties of Tau. Here, we sought to determine the relative contributions of phosphorylation of one or several of the five tyrosine residues in Tau (Tyr-18, -29, -197, -310, and -394) to the regulation of its biophysical, aggregation, and functional properties. We used a combination of site-specific mutagenesis and in vitro phosphorylation by c-Abl kinase to generate Tau species phosphorylated at all five tyrosine residues, all tyrosine residues except Tyr-310 or Tyr-394 (pTau-Y310F and pTau-Y394F, respectively) and Tau phosphorylated only at Tyr-310 or Tyr-394 (4F/pTyr-310 or 4F/pTyr-394). We observed that phosphorylation of all five tyrosine residues, multiple N-terminal tyrosine residues (Tyr-18, -29, and -197), or specific phosphorylation only at residue Tyr-310 abolishes Tau aggregation and inhibits its microtubule- and lipid-binding properties. NMR experiments indicated that these effects are mediated by a local decrease in β-sheet propensity of Tau's PHF6 domain. Our findings underscore Tyr-310 phosphorylation has a unique role in the regulation of Tau aggregation, microtubule, and lipid interactions. These results also highlight the importance of conducting further studies to elucidate the role of Tyr-310 in the regulation of Tau's normal functions and pathogenic properties.

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“…It follows that the repeat structure of the amyloidogenic MTB domain, marked by subtle differences in the electronic configuration of the repeat segments of the main chain, is likely to be one source of the observed diversity of tau-fibril morphology. The differences in conformational propensities and aggregation properties of the four repeats of the MTB domain of tau attracted considerable attention (Perez et al, 1996, 2007; von Bergen et al, 2000; Tokimasa et al, 2005; Naruto et al, 2010; Sogawa et al, 2012, 2014; Lathuillière et al, 2017; Macdonald et al, 2019). To gauge whether and how these differences are indeed related to the differences in backbone polarization, the folding potential FP i is plotted against its “slope” Δ FP i − 1 → i + 1 separately for each repeat, see the FP i vs. Δ FP i − 1 → i + 1 plots in Figure 4, where the side chains of the histidine residues of MTBD are either neutral (the side chain's imidazole ring is not protonated and σ His = −0.2917, Table 1), Figure 4A, or cationic (the side chain's imidazole ring is protonated and σ His+ = 0.2584, Table 1), Figure 4B.…”

Section: Resultsmentioning

confidence: 99%

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

Cieplak

2019

Front. Neurosci.

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Tau-related dementias appear to involve specific to each disease aggregation pathways and morphologies of filamentous tau assemblies. To understand etiology of these differences, here we elucidate molecular mechanism of formation of tau PHFs based on the PMO theory of misfolding and aggregation of pleiomorphic proteins associated with neurodegenerative diseases. In this model, fibrillization of tau is initiated by the coupled binding and folding of the MTB domains that yields antiparallel homodimers, in analogy to folding of split inteins. The free energy of binding is minimized when the antiparallel alignment brings about backbone-backbone H-bonding between the MTBD segments of similar “strand” propensities. To assess these propensities, a function of the NMR shielding tensors of the C α atoms is introduced as the folding potential function FP i ; the C α tensors are obtained by the quantum mechanical modeling of protein secondary structure (GIAO//B3LYP/D95 ** ). The calculated FP i plots show that the “strand” propensities of the MBTD segments, and hence the homodimer's register, can be affected by the relatively small changes in the environment's pH, as a result of protonation of MBTD's conserved histidines. The assembly of the antiparallel tau dimers into granular aggregates and their subsequent conversion into the parallel cross-β structure of paired helical filaments is expected to follow the same path as the previously described fibrillization of Aβ. Consequently, the core structure of the nascent tau fibril is determined by the register of the tau homodimer. This model accounts for the reported differences in (i) fibril-core structure of in vivo and in vitro filaments, (ii) cross-seeding of isoforms, (iii) effects of reducing/non-reducing conditions, (iv) effects of PHF6 mutations, and (v) homologs' aggregation properties. The proposed model also suggests that in contrast to Alzheimer's and chronic traumatic encephalopathy disease, the assembly of tau prions in Pick's disease would be facilitated by a moderate drop in pH that accompanies e.g., transit in the endosomal system, inflammation response or an ischemic injury.

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CH–π interaction in VQIVYK sequence elucidated by NMR spectroscopy is essential for PHF formation of tau

Cited by 19 publications

References 29 publications

Conformational Evolution of Molecular Signatures during Amyloidogenic Protein Aggregation

Conformational Evolution of Molecular Signatures during Amyloidogenic Protein Aggregation

Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

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