Protein structural and surface water rearrangement constitute major events in the earliest aggregation stages of tau

Pavlova, Ànna; Cheng, Chi‐Yuan; Kinnebrew, Maia; Lew, John I.; Dahlquist, Frederick W.; Han, Songi

doi:10.1073/pnas.1504415113

Cited by 74 publications

(105 citation statements)

References 46 publications

(105 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whatever mechanism induces this misfolding step, it is followed by a cascade of aggregation events leading to the fibrillization of S* species. A recent report shows that dynamic aggregation intermediates that form within minutes of initiating aggregation constitute >40–70% of the total tau population26, while this study finds the S* conformers to constitute >50% of the total tau population, again within minutes of initiating aggregation. This shows that we cannot definitely differentiate whether the S-to-S* conformational changes precede the formation of soluble aggregation intermediates or vice versa — to do so require a fast-freeze method to quantitatively analyze the S-to-S* transformation kinetics which is outside the scope of this paper, and is thus left for future studies.…”

Section: Discussioncontrasting

confidence: 71%

“…2 panel b) reveals a short 303-to-316 distance of 3.38 nm in Δtau187, in solution state. Again, the PHF6 region dramatically extends to an average distance of 4.1 nm, within minutes upon heparin addition, well before macroscopic aggregates or any fibrillar species are detectable26. The DEER-derived distance distribution is consistent with the posed 2-state model, in which the S state quantitatively transform into S* state populations.…”

Section: Resultssupporting

confidence: 65%

See 1 more Smart Citation

Signature of an aggregation-prone conformation of tau

Eschmann

Georgieva

Ganguly

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 71%

Section: Resultssupporting

confidence: 65%

Signature of an aggregation-prone conformation of tau

Eschmann

Georgieva

Ganguly

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…This indicates that diverse β structures may be readily accessible at the physiological condition, consistent with previous experimental observations that Tau aggregates as β sheet structures. 59, 60 …”

Section: Resultsmentioning

confidence: 99%

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Dong

Luo

Chen

2017

J. Chem. Inf. Model.

164

189

View full text Add to dashboard Cite

Intrinsically disordered proteins (IDPs) or intrinsically disordered regions have not fixed tertiary structure, but play key roles in signal regulation, molecule recognition, and drug target. However it is difficult to study the structure and function of IDPs by traditional experimental methods because of their diverse conformations. Limitations of current generic protein force fields and solvent models were reported in the previous simulations of IDPs. We have also explored to overcome these limitations by developing ff99IDPs and ff14IDPs force fields to correct the dihedral distribution for eight disordered promoting residues often observed in IDPs and found encouraging improvements. Here, we extend our correction of backbone dihedral terms to all 20 naturally occurring amino acids in the IDP-specific force field (ff14IDPSFF) to further improve the quality in the modeling of IDPs. Extensive tests of seven IDPs and 14 unstructured short peptides show that the simulated Cα chemical shifts with the ff14IDPSFF force field are in quantitative agreement with those from NMR experiment and are more accurate than the base generic force field and also our previous ff14IDPs that only corrects the eight disorder-promoting amino acids. The influences of solvent models were also investigated and found to be less important. Finally our explicit solvent MD simulations further show that ff14IDPSFF can still be used to model structural and dynamical properties of two tested folded proteins, with a slightly better agreement in the loop regions for both structural and dynamical properties. These findings confirm that the newly developed IDP-specific force field ff14IDPSFF can improve the conformer sampling of intrinsically disordered proteins.

show abstract

“…The hydration dynamics on the surface of ΔTau-187 monomers were measured on sites 313, 316, 322, 400, and 404 17 , of α-synuclein measured at sites 77, 81, 85, 86, 90, 93, 95, 98, 100, 101, 124, and 136 18 , and of Annexin XII measured at sites 12, 16, 104, 112, 121, 124, 137, 141, 162, 180, and 260 XII 19 . The liposomes systems were prepared in the LUV state and composed of purely DOPC, DPPC, and a 50:50 mixture of DOPC/DPPC.…”

Section: Methodsmentioning

confidence: 99%

Spatially Heterogeneous Surface Water Diffusivity around Structured Protein Surfaces at Equilibrium

et al. 2017

Self Cite

View full text Add to dashboard Cite

Hydration water on the surface of a protein is thought to mediate the thermodynamics of protein-ligand interaction. For hydration water to play a role beyond modulating global protein solubility or stability, the thermodynamic properties of hydration water must reflect on the properties of the heterogeneous protein surface, and thus spatially vary over the protein surface. A potent read-out of local variations in thermodynamic properties of hydration water is its equilibrium dynamics spanning picosecond to nanosecond timescales. In this study, we rely on Overhauser dynamic nuclear polarization (ODNP) to probe the equilibrium hydration water dynamics on the globular protein Chemotaxis Y (CheY), in dilute solution, at select sites located on the protein surface. ODNP reports on site-specific hydration dynamics within 5–10 Å of a label tethered to the biomolecular surface on two separate timescales of motion, corresponding to diffusive water (DW) and protein-water coupled motions referred to as bound water (BW). We find DW dynamics to be highly heterogeneous across the surface of CheY, while also finding significant populations of BW. We identify a significant correlation between DW dynamics and the local hydropathy of the CheY protein surface, as empirically determined by molecular dynamics (MD) simulations, and find the more hydrophobic sites to be hydrated with slower diffusing water. We furthermore compare the DW dynamics and BW population on the surface of CheY to that of another globular protein Annexin XII (Anx), two intrinsically disordered proteins (IDPs) ΔTau-187 and α-synuclein, CheY-inspired 5 residue peptides, polyproline-based peptides with systematic charge variation, and DPPC/DOPC liposomes. The DW dynamics on Anx is similarly heterogeneous as on CheY, and there is significant BW population on both Anx and CheY. In contrast, DW dynamics is relatively homogeneous on IDP and liposome surfaces, while BW is entirely absent. The heterogeneity in hydration water properties suggests that a structured protein surface has the capacity to encode information into its hydration water to mediate the free energy of interactions involving the protein surface.

show abstract

Protein structural and surface water rearrangement constitute major events in the earliest aggregation stages of tau

Cited by 74 publications

References 46 publications

Signature of an aggregation-prone conformation of tau

Signature of an aggregation-prone conformation of tau

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Spatially Heterogeneous Surface Water Diffusivity around Structured Protein Surfaces at Equilibrium

Contact Info

Product

Resources

About