TMAO Promotes Fibrillization and Microtubule Assembly Activity in the C-Terminal Repeat Region of Tau

Scaramozzino, Francesca; Peterson, Dylan W.; Farmer, Patrick J.; Gerig, J. T.; Graves, Donald J.; Lew, John I.

doi:10.1021/bi052167g

Cited by 75 publications

(73 citation statements)

References 53 publications

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“…Aggregation on experimental time scales remained heparin-dependent. These results are in agreement with previous work on a longer tau segment containing the entire microtubule binding repeat region, and the carboxyl-terminal tail of the protein (Tau187) (28). To further investigate the effects of TMAO on R2/wt aggregation, we also performed simulations of R2/wt dimerization in the presence of TMAO.…”

Section: Resultssupporting

confidence: 89%

Regulation and aggregation of intrinsically disordered peptides

Levine¹,

Larini²,

LaPointe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

195

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Intrinsically disordered proteins (IDPs) are a unique class of proteins that have no stable native structure, a feature that allows them to adopt a wide variety of extended and compact conformations that facilitate a large number of vital physiological functions. One of the most well-known IDPs is the microtubule-associated tau protein, which regulates microtubule growth in the nervous system. However, dysfunctions in tau can lead to tau oligomerization, fibril formation, and neurodegenerative disease, including Alzheimer's disease. Using a combination of simulations and experiments, we explore the role of osmolytes in regulating the conformation and aggregation propensities of the R2/wt peptide, a fragment of tau containing the aggregating paired helical filament (PHF6*). We show that the osmolytes urea and trimethylamine N-oxide (TMAO) shift the population of IDP monomer structures, but that no new conformational ensembles emerge. Although urea halts aggregation, TMAO promotes the formation of compact oligomers (including helical oligomers) through a newly proposed mechanism of redistribution of water around the perimeter of the peptide. We put forth a "superposition of ensembles" hypothesis to rationalize the mechanism by which IDP structure and aggregation is regulated in the cell.protein folding | intrinsically disordered proteins | molecular dynamics simulations | osmolytes | tau protein M ost proteins in the human body have a well-defined, stable three-dimensional structure that is intimately tied to their physiological function. In the past few decades however, researchers have also identified a class of proteins that are natively unstructured. The latter, often referred to as intrinsically disordered proteins (IDPs) (1), are widespread and have the ability to quickly change their conformations to participate in a variety of biological processes. IDPs typically contain multiple charged side chains and few hydrophobic residues. Despite these characteristics, IDPs are not typically found in extended states but rather populate compact states due to hydrogen bonds and salt bridges (2, 3). IDP structures are highly regulated in the cell, and aberrant regulation often results in protein aggregation.In this paper we consider the effect of external agents, specifically osmolytes, in regulating IDP structure and aggregation properties. To carry out this study, we focused on the microtubule-associated protein tau, a soluble (4), archetypical IDP found in the nervous system that helps regulate and stabilize microtubules (5, 6). When the regulation of tau structure and activity is compromised, tau loses its ability to bind to microtubules, and disassociated tau proteins can aggregate into supramolecular assemblies with a cross-β structure (7-9) typical of amyloid fibers. This aggregation process is a pathological hallmark of Alzheimer's disease and other forms of dementia known as tauopathies (10, 11). We consider here a segment of tau, the R2/wt fragment 273 GKVQIINKKLDL 284 , which contains the highly aggregation ...

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Section: Resultssupporting

confidence: 89%

Regulation and aggregation of intrinsically disordered peptides

Levine¹,

Larini²,

LaPointe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

195

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“…4,5 The study of TMAO's properties has proved to be useful in providing insight into fundamental aspects of protein stability, as well as providing important concepts involving numerous diseases. [6][7][8][9][10] Transfer free energy values for sidechains and peptide backbone, DG tr , quantify the thermodynamic consequences of solvating a protein species in a cosolvent solution relative to pure water. Based on the transfer model and experimental DG tr for these groups it has been proposed that osmolytes exert their effect on protein stability primarily via the protein backbone.…”

Section: Introductionmentioning

confidence: 99%

Backbone additivity in the transfer model of protein solvation

et al. 2010

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The transfer model implying additivity of the peptide backbone free energy of transfer is computationally tested. Molecular dynamics simulations are used to determine the extent of change in transfer free energy (DG tr ) with increase in chain length of oligoglycine with capped end groups. Solvation free energies of oligoglycine models of varying lengths in pure water and in the osmolyte solutions, 2M urea and 2M trimethylamine N-oxide (TMAO), were calculated from simulations of all atom models, and DG tr values for peptide backbone transfer from water to the osmolyte solutions were determined. The results show that the transfer free energies change linearly with increasing chain length, demonstrating the principle of additivity, and provide values in reasonable agreement with experiment. The peptide backbone transfer free energy contributions arise from van der Waals interactions in the case of transfer to urea, but from electrostatics on transfer to TMAO solution. The simulations used here allow for the calculation of the solvation and transfer free energy of longer oligoglycine models to be evaluated than is currently possible through experiment. The peptide backbone unit computed transfer free energy of 254 cal/mol/M compares quite favorably with 243 cal/mol/M determined experimentally.

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“…Δtau187 forms neat fibrils (see Supplementary Fig. S1) with cross-β sheet structures characteristics of full length tau20. The PHF6 * (VQIINK) segment as part of the second MTB repeat, R2, and PHF6 (VQIVYK) as part of the third MTB repeat, R3, are the key building blocks that pack to form the β-sheet structured core of mature tau fibrils16202122.…”

mentioning

confidence: 99%

Signature of an aggregation-prone conformation of tau

Eschmann

Georgieva

Ganguly

et al. 2017

Sci Rep

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The self-assembly of the microtubule associated tau protein into fibrillar cell inclusions is linked to a number of devastating neurodegenerative disorders collectively known as tauopathies. The mechanism by which tau self-assembles into pathological entities is a matter of much debate, largely due to the lack of direct experimental insights into the earliest stages of aggregation. We present pulsed double electron-electron resonance measurements of two key fibril-forming regions of tau, PHF6 and PHF6*, in transient as aggregation happens. By monitoring the end-to-end distance distribution of these segments as a function of aggregation time, we show that the PHF6(*) regions dramatically extend to distances commensurate with extended β-strand structures within the earliest stages of aggregation, well before fibril formation. Combined with simulations, our experiments show that the extended β-strand conformational state of PHF6(*) is readily populated under aggregating conditions, constituting a defining signature of aggregation-prone tau, and as such, a possible target for therapeutic interventions.

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TMAO Promotes Fibrillization and Microtubule Assembly Activity in the C-Terminal Repeat Region of Tau

Cited by 75 publications

References 53 publications

Regulation and aggregation of intrinsically disordered peptides

Regulation and aggregation of intrinsically disordered peptides

Backbone additivity in the transfer model of protein solvation

Signature of an aggregation-prone conformation of tau

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