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Fibril formation by amyloid-beta proteins may involve beta-helical protofibrils
1Department of Dermatology, University of Iowa College of Medicine, Iowa City 52242, USA.
Abstract:
We have proposed that amyloid fibrils contain subunits (protofibrils) that are formed from beta-strands wound into continuous 2-3 nm-diameter beta-helices. Subsequent lateral aggregation of the beta-helices to form the widely observed 5-12 nm-diameter fibrils could be promoted by hydrophobic residues on the exterior of the postulated beta-helix. A number of short peptide fragments of the amyloid-beta (A beta) proteins, such as A beta34-42 [LMVGGVVIA], the nine-residue, carboxyl-terminal portion of A beta1-42, can also form amyloid fibrils. In the present study, it was found that a beta-helix formed from A beta34-42 accounts for features suggested by published rotational resonance solid-state NMR data, including an anomalous conformation about the Gly-37-Gly-38 region and exaggerated pleating. An analogue of A beta34-42 was synthesized in which the hydrophobic groups on the exterior of the postulated beta-helix were replaced with glutamates, giving LEVGGVEIE. The analogue was completely soluble at pH 7, but at pH 2.5 it produced 2-2.5 nm-diameter fibrils which did not associate into larger-diameter bundles. The results of this study support the proposal that amyloid fibrils are formed from beta-helical subunits.
Insights
Amyloid fibrils are proposed to form from beta-helical subunits. Modifying the exterior of these beta-helices with charged residues prevents larger fibril formation, supporting the beta-helix subunit model for amyloid.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Amyloid fibrils are implicated in neurodegenerative diseases.
- Previous models proposed amyloid fibrils are formed from beta-helical subunits.
Purpose of the Study:
- To investigate the role of beta-helical subunits in amyloid fibril formation.
- To test the hypothesis that hydrophobic residues on beta-helices promote fibril aggregation.
Main Methods:
- Synthesized a modified amyloid-beta (A beta) 34-42 peptide with glutamate residues replacing exterior hydrophobic groups.
- Analyzed the solubility and fibril formation of the modified peptide at different pH levels.
- Characterized the resulting fibrils using biophysical techniques.
Main Results:
- The modified peptide (LEVGGVEIE) remained soluble at pH 7.
- At pH 2.5, the modified peptide formed small fibrils (2-2.5 nm) that did not aggregate into larger bundles.
- These findings align with the beta-helix subunit model and the role of hydrophobic interactions.
Conclusions:
- The study supports the model of amyloid fibrils being composed of beta-helical subunits.
- Modulating surface hydrophobicity of beta-helices can control fibril assembly.
- This provides insights into the structural basis of amyloid formation.