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Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy
Published on: November 30, 2018
Stability of a Recently Found Triple-β-Stranded Aβ1-42 Fibril Motif
Wenhui Xi1, Wenhua Wang1, Gabrielle Abbott1
1Department of Chemistry and Biochemistry, University of Oklahoma , Norman, Oklahoma 73019, United States.
Abstract:
Amyloid-β peptides form polymorphous amyloid fibrils are correlated with the pathogenesis of Alzheimer's disease. Recently, a new ssNMR high-resolution structure has been reported for wild-type Aβ1-42 fibrils that is characterized by a strand-turn-strand-turn-strand motif instead of the U-shape form seen in previously known wild-type Aβ-fibril structures. Analyzing molecular dynamics simulations we comment on the relative weight of the new fibril structure and present evidence that its stability depends on hydrophobic contacts involving the C-terminal residues I41 and A42, but not on the salt bridge K28-A42. We further argue that Aβ1-42 peptides with this structure may assemble in fibrils with a 2-fold packing symmetry and discuss two possible arrangements.
Insights
New Alzheimer's disease research reveals a novel amyloid-β1-42 fibril structure. Molecular dynamics simulations suggest this structure
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Amyloid-β (Aβ) fibrils are implicated in Alzheimer's disease pathogenesis.
- Previous Aβ1-42 fibril structures exhibited a U-shape.
- A new high-resolution ssNMR structure reveals a distinct strand-turn-strand-turn-strand motif.
Purpose of the Study:
- To analyze the stability and implications of the newly reported Aβ1-42 fibril structure.
- To investigate the role of specific residues and interactions in fibril stability.
- To explore potential fibril assembly and packing symmetries.
Main Methods:
- Solid-state Nuclear Magnetic Resonance (ssNMR) data analysis.
- Molecular Dynamics (MD) simulations.
- Structural analysis of amyloid-β1-42 (Aβ1-42) fibrils.
Main Results:
- The new Aβ1-42 fibril structure features a strand-turn-strand-turn-strand motif.
- Fibril stability is dependent on hydrophobic contacts involving C-terminal residues I41 and A42.
- The salt bridge between K28 and A42 does not significantly contribute to the stability of this structure.
- Evidence suggests this Aβ1-42 structure may form fibrils with 2-fold packing symmetry.
Conclusions:
- The novel Aβ1-42 fibril structure offers new insights into Alzheimer's disease mechanisms.
- Hydrophobic interactions at the C-terminus are critical for the stability of this fibril conformation.
- Understanding these structural variations is key to developing targeted Alzheimer's therapies.
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