Simulation of the β‐ to α‐sheet transition results in a twisted sheet for antiparallel and an α‐nanotube for parallel strands: Implications for amyloid formation

Hayward, Steven; Milner‐White, E. James

doi:10.1002/prot.23154

Cited by 18 publications

(21 citation statements)

References 52 publications

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“…Previous studies have noted that these chemical shifts are indicative of β-sheet rather than α-helical or random coil structure. However, some argue that polyQ aggregation may involve a nonstandard secondary structure, known as α-sheet, which may be indistinguishable from β-sheet by its NMR shifts (20,21). To test this assertion, we did chemical shift-independent torsion angle measurements (22) and found unambiguous evidence for a β-sheet conformation.…”

Section: Resultsmentioning

confidence: 99%

Huntingtin exon 1 fibrils feature an interdigitated β-hairpin–based polyglutamine core

Hoop

Lin

Kar

et al. 2016

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

156

278

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Polyglutamine expansion within the exon1 of huntingtin leads to protein misfolding, aggregation, and cytotoxicity in Huntington's disease. This incurable neurodegenerative disease is the most prevalent member of a family of CAG repeat expansion disorders. Although mature exon1 fibrils are viable candidates for the toxic species, their molecular structure and how they form have remained poorly understood. Using advanced magic angle spinning solid-state NMR, we directly probe the structure of the rigid core that is at the heart of huntingtin exon1 fibrils and other polyglutamine aggregates, via measurements of long-range intramolecular and intermolecular contacts, backbone and side-chain torsion angles, relaxation measurements, and calculations of chemical shifts. These experiments reveal the presence of β-hairpin-containing β-sheets that are connected through interdigitating extended side chains. Despite dramatic differences in aggregation behavior, huntingtin exon1 fibrils and other polyglutamine-based aggregates contain identical β-strand-based cores. Prior structural models, derived from X-ray fiber diffraction and computational analyses, are shown to be inconsistent with the solid-state NMR results. Internally, the polyglutamine amyloid fibrils are coassembled from differently structured monomers, which we describe as a type of "intrinsic" polymorphism. A stochastic polyglutamine-specific aggregation mechanism is introduced to explain this phenomenon. We show that the aggregation of mutant huntingtin exon1 proceeds via an intramolecular collapse of the expanded polyglutamine domain and discuss the implications of this observation for our understanding of its misfolding and aggregation mechanisms.solid-state NMR | Huntington's disease | amyloid disease | protein aggregation | amyloid

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Section: Resultsmentioning

confidence: 99%

Huntingtin exon 1 fibrils feature an interdigitated β-hairpin–based polyglutamine core

Hoop

Lin

Kar

et al. 2016

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

156

278

View full text Add to dashboard Cite

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“…Sheets for simulation were constructed from straight untwisted strands (with exactly 180° rotation about the strand helical axis per residue) for which excellent inter-strand hydrogen bonding can be achieved along the whole length. Such a strand with standard bond angles, standard ω torsions angles, and repeating (ϕ, ψ) angles satisfies the equation ψ=−2arctan(0.92tan(ϕ/2)) (Hayward and Milner-White, 2011). A straight strand of 40 alanine residues was constructed using the angles, (-120°,115.8°), which satisfy this equation and also are close to the average (ϕ, ψ)…”

Section: Construction Of β-Sheets For Simulationmentioning

confidence: 99%

Multi-strand β-sheet of Alzheimer Aβ(1–40) folds to β-strip helix: implication for protofilament formation

Hayward

Kitao

2018

Journal of Biomolecular Structure and Dynamics

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X-ray fibre diffraction experiments on Alzheimer Aβ(1-40) fibrils (Fraser et al. Biochemistry 31, 1992; Malinchik et al. Biophysical Journal, 74, 1998) indicated protofilaments with tilted β-strands rather than strands oriented perpendicular to the fibril axis as is usually interpreted from cross-β patterns. The protofilament width and tilt angle determined by these experiments were used to predict a β-strip helix model - a β-helix-like structure in which multiple identical polypeptide molecules assemble in-register to form a helical sheet structure such that the outer strands 1 and m join with a register shift t - with m = 11 and t = 22. Starting from untwisted β-sheets comprising 10, 11 and 12 strands, multiple explicit solvent Molecular Dynamics simulations were performed to determine whether the sheets form β-strip helices matching the dimensions of the experimentally measured protofilament. In the simulations, the predicted 11-strand sheets curled up to form a closed β-strip helix like structure with dimensions matching experimental values, whereas the 10- and 12-strand sheets did not form a closed helical structure. However, the 12-strand structure did show similarity to a cross-β structure determined by a solid-state NMR experiment. The 11-strand β-strip helix resembles a trans-membrane β-barrel which could explain the ability of small oligomers of Aβ(1-40) to form toxic ion channels. A further consequence of opposite sides of the 11-strand strip coming together at a register shift of 22 is end-to-end joins between neighbouring β-strip helices, resulting in a protofilament that keeps growing in both directions.

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“…Combining this topological information allows us to convert from internal coordinates to Cartesian coordinates for any given loop. In order to transform from a molecule-based coordinate system to a system-based coordinate system a virtual atom was used as described elsewhere 15 .…”

Section: Side Chain Internal Variablesmentioning

confidence: 99%

Monte Carlo Sampling with Linear Inverse Kinematics for Simulation of Protein Flexible Regions

Hayward

Kitao

2015

J. Chem. Theory Comput.

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A Monte Carlo linear inverse-kinematics method for the simulation of protein chains with fixed ends is introduced. It includes backbone bond-angle bending and simultaneous loop and ring closure to allow full proline ring flexibility. An obstacle to linear null-space methods is the eventual drift of the end group. Maintenance of the end group at its initial position by occasional reset is performed in a way that is consistent with the overall methodology and minimally disruptive to the current conformation. The implementation permitted multiple rigid regions within the chain, enabling the simulation of domain movements where domains are rigid bodies connected by flexible interdomain regions. The method was tested on polyalanine, polyglycine, loop 6 of triosephosphate isomerase, and glutamine binding protein. Simulations of glutamine binding protein, where only 11 of the 226 residues at the interdomain bending regions were flexible, accurately reproduced the experimentally determined domain movement.

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Simulation of the β‐ to α‐sheet transition results in a twisted sheet for antiparallel and an α‐nanotube for parallel strands: Implications for amyloid formation

Cited by 18 publications

References 52 publications

Huntingtin exon 1 fibrils feature an interdigitated β-hairpin–based polyglutamine core

Huntingtin exon 1 fibrils feature an interdigitated β-hairpin–based polyglutamine core

Multi-strand β-sheet of Alzheimer Aβ(1–40) folds to β-strip helix: implication for protofilament formation

Monte Carlo Sampling with Linear Inverse Kinematics for Simulation of Protein Flexible Regions

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