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Nanoscale flexibility parameters of Alzheimer amyloid fibrils determined by electron cryo-microscopy.

Sachse C, Grigorieff N, Fändrich M - Angew. Chem. Int. Ed. Engl. (2010)

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory of Molecular Biology, Cambridge, UK.

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Amyloid fibrils are fibrillar polypeptide aggregates consisting of a cross-β structure., The rigidity and stability of these fibrils contributes to their natural pathogenicity or functionality and has suggested potential applications in bionanotechnology. – Yet, amyloid fibrils can occur in different morphologies with unique mechanical and flexible characteristics. – Herein, we use electron cryo-microscopy (cryo-EM) to characterize these nanoscale structural properties... Whereas the distinction between F120 and F140 fibrils remains arbitrary, the two subpopulations consist of a sufficiently large data set for a medium-resolution 3D reconstruction and for measurement of the nanoscale elastic properties... Reconstructed F120 and F140 fibrils present effectively the same cross-section (Figure 3)... Our measurements imply that F120 and F140 fibrils possess very similar, if not identical, torsional properties (torsional rigidity c and torsional persistence length lc; Table 2 in the Supporting Information)... The torsional rigidities of F120 and F140 fibrils are very similar and produce the same shear modulus G within error margins [Eq.  (1), Table 2 in the Supporting Information)... We have compared the calculated material moduli with literature data... Exact numeric values should be considered carefully, however, owing to possible effects of the method of analysis... The Young’s moduli Y of F120 and F140 fibrils (90 and 320 MPa, respectively) are close to the observed values for filamentous proteins, such as SCF (50 MPa), but are somewhat lower than figures of microtubuli and actin (1 and 3 GPa, respectively)... The material constants of F120 and F140 fibrils differ more profoundly from those reported recently for insulin amyloid fibrils (shear modulus G=130 MPa, Young’s modulus Y=6 GPa)... By contrast, the persistence length (42 μm) and bending rigidity (1.7×10 N m) of insulin fibrils are remarkably similar to those of Aβ(1–40) fibrils... Since no 3D reconstruction of the analyzed insulin fibrils was reported, their cross-sectional structure cannot be compared easily with the structure of the Aβ(1–40) fibrils used here... While our data cannot confirm the existence of unusually high nanoscale material constants for the analyzed Aβ(1–40) fibrils, we find that the shape-dependent properties polar moment of inertia Iz and moment of inertia are significantly greater for the analyzed Aβ(1–40) fibrils than for area-normalized cross-sections of other protein filaments (Figure 4 B)... This conclusion is consistent with the fact that amyloid pathogenicity arises, at least partially, from the distortion or disruption of naturally elastic and flexible tissues, such as cardiac ventricles or blood vessel walls... Further work will be required, however, to delineate the cellular pathways by which these reactions result in the death of affected cells.

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Cross-section of F120 (A) and F140 fibrils (B). C) Difference map F140−F120. Negative peaks: orange=2σ, red=3σ. Positive peaks: light blue=2σ, blue=3σ.
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fig03: Cross-section of F120 (A) and F140 fibrils (B). C) Difference map F140−F120. Negative peaks: orange=2σ, red=3σ. Positive peaks: light blue=2σ, blue=3σ.

Mentions: To further analyze these structural differences, two subpopulations were defined, termed here F120 and F140 fibrils. F140 fibrils show mean d values of (140±10) nm (Figure 2 B), and their 3D structure was reconstructed previously at approximately 8 Å resolution.10, 11 F120 fibrils possess an average d value of (120±10) nm (Figure 2 B). The structure of F120 fibrils is determined here at approximately 10 Å resolution (Figure 3 A, B, Figure 2 in the Supporting Information). Whereas the distinction between F120 and F140 fibrils remains arbitrary, the two subpopulations consist of a sufficiently large data set for a medium-resolution 3D reconstruction and for measurement of the nanoscale elastic properties. Reconstructed F120 and F140 fibrils present effectively the same cross-section (Figure 3). Hence, the conformational differences of the peptides forming F120 and F140 fibrils are too small to be revealed at the current levels of structural resolution. These data imply that the systematic variations in the crossover distances of different fibrils (Figure 2 A) occur within fibrils that all belong to the same basic morphology. In other words, different fibrils of the same morphology can occur with different torsional properties.


Nanoscale flexibility parameters of Alzheimer amyloid fibrils determined by electron cryo-microscopy.

Sachse C, Grigorieff N, Fändrich M - Angew. Chem. Int. Ed. Engl. (2010)

Cross-section of F120 (A) and F140 fibrils (B). C) Difference map F140−F120. Negative peaks: orange=2σ, red=3σ. Positive peaks: light blue=2σ, blue=3σ.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913414&req=5

fig03: Cross-section of F120 (A) and F140 fibrils (B). C) Difference map F140−F120. Negative peaks: orange=2σ, red=3σ. Positive peaks: light blue=2σ, blue=3σ.
Mentions: To further analyze these structural differences, two subpopulations were defined, termed here F120 and F140 fibrils. F140 fibrils show mean d values of (140±10) nm (Figure 2 B), and their 3D structure was reconstructed previously at approximately 8 Å resolution.10, 11 F120 fibrils possess an average d value of (120±10) nm (Figure 2 B). The structure of F120 fibrils is determined here at approximately 10 Å resolution (Figure 3 A, B, Figure 2 in the Supporting Information). Whereas the distinction between F120 and F140 fibrils remains arbitrary, the two subpopulations consist of a sufficiently large data set for a medium-resolution 3D reconstruction and for measurement of the nanoscale elastic properties. Reconstructed F120 and F140 fibrils present effectively the same cross-section (Figure 3). Hence, the conformational differences of the peptides forming F120 and F140 fibrils are too small to be revealed at the current levels of structural resolution. These data imply that the systematic variations in the crossover distances of different fibrils (Figure 2 A) occur within fibrils that all belong to the same basic morphology. In other words, different fibrils of the same morphology can occur with different torsional properties.

View Article: PubMed Central - PubMed

Affiliation: MRC Laboratory of Molecular Biology, Cambridge, UK.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Amyloid fibrils are fibrillar polypeptide aggregates consisting of a cross-β structure., The rigidity and stability of these fibrils contributes to their natural pathogenicity or functionality and has suggested potential applications in bionanotechnology. – Yet, amyloid fibrils can occur in different morphologies with unique mechanical and flexible characteristics. – Herein, we use electron cryo-microscopy (cryo-EM) to characterize these nanoscale structural properties... Whereas the distinction between F120 and F140 fibrils remains arbitrary, the two subpopulations consist of a sufficiently large data set for a medium-resolution 3D reconstruction and for measurement of the nanoscale elastic properties... Reconstructed F120 and F140 fibrils present effectively the same cross-section (Figure 3)... Our measurements imply that F120 and F140 fibrils possess very similar, if not identical, torsional properties (torsional rigidity c and torsional persistence length lc; Table 2 in the Supporting Information)... The torsional rigidities of F120 and F140 fibrils are very similar and produce the same shear modulus G within error margins [Eq.  (1), Table 2 in the Supporting Information)... We have compared the calculated material moduli with literature data... Exact numeric values should be considered carefully, however, owing to possible effects of the method of analysis... The Young’s moduli Y of F120 and F140 fibrils (90 and 320 MPa, respectively) are close to the observed values for filamentous proteins, such as SCF (50 MPa), but are somewhat lower than figures of microtubuli and actin (1 and 3 GPa, respectively)... The material constants of F120 and F140 fibrils differ more profoundly from those reported recently for insulin amyloid fibrils (shear modulus G=130 MPa, Young’s modulus Y=6 GPa)... By contrast, the persistence length (42 μm) and bending rigidity (1.7×10 N m) of insulin fibrils are remarkably similar to those of Aβ(1–40) fibrils... Since no 3D reconstruction of the analyzed insulin fibrils was reported, their cross-sectional structure cannot be compared easily with the structure of the Aβ(1–40) fibrils used here... While our data cannot confirm the existence of unusually high nanoscale material constants for the analyzed Aβ(1–40) fibrils, we find that the shape-dependent properties polar moment of inertia Iz and moment of inertia are significantly greater for the analyzed Aβ(1–40) fibrils than for area-normalized cross-sections of other protein filaments (Figure 4 B)... This conclusion is consistent with the fact that amyloid pathogenicity arises, at least partially, from the distortion or disruption of naturally elastic and flexible tissues, such as cardiac ventricles or blood vessel walls... Further work will be required, however, to delineate the cellular pathways by which these reactions result in the death of affected cells.

Show MeSH