The solution structure of theC-terminal segment of tau protein

Esposito, Gennaro; Viglino, Paolo; Novák, Michal; Cattaneo, Antonino

doi:10.1002/1099-1387(200011)6:11<550::aid-psc272>3.0.co;2-s

Cited by 16 publications

(10 citation statements)

References 56 publications

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“…The former condition reproduces the environment of the peptides in solution, while the latter is frequently employed to mimic the hydrophobic microenvironment of a peptide domain within a folded protein structure (). As shown in Figure A, and as predicted from previous reports ( , ), tau 422−441 exhibits little secondary structure in aqueous buffer but in the hydrophobic environment afforded by 36% TFE assumes substantial helical structure, as assessed by the development of minima at 208 and 223 nm. The scrambled peptide, RND1, had an equal to or greater propensity for helix formation (Figure B), and the RND2 peptide showed little tendency to assume an ordered conformation (Figure C).…”

Section: Resultssupporting

confidence: 84%

“…Helical Conformation of the C-Terminus Is Important for Inhibition of Tau Polymerization. Although there is evidence that the tau molecule possesses minimal secondary structure in solution ( , ), there is also evidence that the C-terminal region is capable of adopting an α-helical conformation ( , ). Moreover, a helical wheel projection predicts that such a conformation would result in an amphipathic helix, with opposite polar and nonpolar faces (Figure A).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment

et al. 2003

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Abnormal aggregation of the microtubule-associated protein, tau, occurs in many neurodegenerative diseases, making it important to understand the mechanisms of tau polymerization. Previous work has indicated that the C-terminal region of tau inhibits polymerization in vitro, and a growing body of evidence implicates caspase cleavage of tau at Asp 421 in the C-terminus as an important inducer of tau polymerization in Alzheimer's disease. In the present study, we provide evidence that the C-terminal peptide fragment produced by caspase cleavage inhibits tau polymerization, suggesting that caspase cleavage of tau enhances its polymerization by removing the inhibitory control element. Moreover, we provide evidence that the peptide assumes an alpha-helical configuration and inhibits tau assembly by interacting with residues 321-375 in the microtubule binding repeat region. These findings indicate that formation of the fibrillar pathologies during the course of Alzheimer's disease may be driven or sustained by apoptotic events leading to caspase activation.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment

et al. 2003

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“…In fact, abnormally hyperphosphorylated tau isolated from human AD brains can self-assemble into PHFs in vitro [93]. Truncation can also affect aggregation, as tau fragments that contain the repeat domain have a higher tendency for aggregation [94], a process that is related with pathology [95]. Regardless of the aggregation process, these aggregates can spread throughout the brain, expanding the pathology [96,97].…”

Section: Aggregation and Characteristics Of Pathological Taumentioning

confidence: 99%

Pharmacological Modulators of Tau Aggregation and Spreading

Dominguez-Meijide

Vasili²,

Outeiro

2020

Brain Sciences

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Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.

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“…Despite a number of biophysical structural studies on Tau, or Tau fragments, in vitro (Woody et al, 1983; Wischik et al, 1988a,b; Hasegawa et al, 1998; Esposito et al, 2000; Barghorn et al, 2005; Kuret et al, 2005; Kadavath et al, 2015a,b) little is known about full length Tau conformations in the presence or absence of MTs in the context of live cells.…”

Section: Introductionmentioning

confidence: 99%

The Distance between N and C Termini of Tau and of FTDP-17 Mutants Is Modulated by Microtubule Interactions in Living Cells

Primio

Quercioli

Siano

et al. 2017

Front. Mol. Neurosci.

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The microtubule (MT)-associated protein Tau is a natively unfolded protein, involved in a number of neurodegenerative disorders, collectively called tauopathies, aggregating in neurofibrillary tangles (NFT). It is an open question how the conversion from a MT bound molecule to an aggregation-prone Tau species occurs and, also, if and how tauopathy-related mutations affect its behavior in the cell. To address these points, we exploited a genetically encoded FRET sensor based on the full length Tau protein, to monitor in real time Tau conformational changes in different conditions in live cells. By studying the FRET signal we found that soluble Tau molecules, detached from MTs, display an unfolded structure. On the contrary, we observed an increased FRET signal generated by Tau monomers bound to MT, indicating that the association with MTs induced a folding of Tau protein, decreasing the distance between its N and C termini. We exploited the FRET sensor to investigate the impact of FTDP-17 mutations and of phosphorylation-site mutations on Tau folding and mobility in live cells. We demonstrated that the FTDP-17 Tau mutations weaken the interaction of Tau with cellular MTs, shifting the equilibrium towards the soluble pool while, conversely, phosphorylation site mutations shift the equilibrium of Tau towards the MT-bound state and a more closed conformation.

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The solution structure of theC-terminal segment of tau protein

Cited by 16 publications

References 56 publications

Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment

Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment

Pharmacological Modulators of Tau Aggregation and Spreading

The Distance between N and C Termini of Tau and of FTDP-17 Mutants Is Modulated by Microtubule Interactions in Living Cells

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