Investigating a Novel Neurodegenerative Disease Toxic Mechanism Involving Lipid Binding Specificity of Amyloid
Sarah S Hirschbeck1, Edward T Lindberg1, Joshua H Jang2
1Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, United States.
Abstract:
Exploring the mechanisms underlying the toxicity of amyloid oligomers (AOs) presents a significant opportunity for discovering cures and developing treatments for neurodegenerative diseases. Recently, using a combination of ion mobility spectrometry-mass spectrometry (IMS-MS) and X-ray crystallography (XRC), we showed that the peptide KVKVLWDVIEV, which is the G95W mutant of αB-Crystallin (90-100) and abbreviated as G6W, self-assembles up to a dodecamer that structurally resembles lipid transport proteins. The glycine to tryptophan mutation promotes not only larger oligomers and enhanced cytotoxicity in brain slices than the wild type but also a narrow hydrophobic cavity suitable for fatty acid or phospholipid binding. Here, we determine the plausibility of a novel cytotoxic mechanism where the G6W's structural motif could perturb lipid homeostasis by determining its lipid binding selectivity and specificity. We show that the G6W oligomers have a strong affinity toward unsaturated phospholipids with a preference toward phospholipids containing 16-C alkyl chains. Molecular dynamics simulations demonstrate how an unsaturated, 16-C phospholipid fits tightly inside and outside G6W's hydrophobic cavity. This binding is exclusive to the G6W peptide, as other amyloid oligomers with different atomic structures, including its wildtype αB-Crystallin (90-100) and several superoxide dismutase 1 (SOD1) peptides that are known to self-assemble into amyloid oligomers (SOD1P28K and SOD1WG-GW), do not experience the same strong binding affinity. While the existing chaperone-lipid hypothesis on amyloid toxicity suggests amyloid-lipid complexes perforate cell membranes, our work provides a new outlook, indicating that soluble amyloid oligomers disrupt lipid homeostasis via selective protein-ligand interactions. The toxic mechanisms may arise from the formation of unique amyloid oligomer structures assisted by lipid ligands or impaired lipid transports.
Insights
A mutated amyloid oligomer (G6W) selectively binds to specific phospholipids, disrupting lipid homeostasis and potentially causing neurotoxicity. This differs from existing theories on amyloid-lipid interactions in disease.
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Amyloid oligomers (AOs) are implicated in neurodegenerative diseases.
- Understanding AO toxicity mechanisms is crucial for developing treatments.
- The G95W mutant of αB-Crystallin (90-100), abbreviated as G6W, forms larger, more cytotoxic oligomers than wild-type.
Purpose of the Study:
- To investigate a novel cytotoxic mechanism involving G6W's interaction with lipids.
- To determine the lipid binding selectivity and specificity of G6W oligomers.
- To elucidate how G6W perturbs lipid homeostasis.
Main Methods:
- Ion mobility spectrometry-mass spectrometry (IMS-MS) and X-ray crystallography (XRC) were used to characterize G6W oligomers.
- Lipid binding assays were performed to assess affinity and specificity.
- Molecular dynamics simulations were employed to visualize peptide-lipid interactions.
Main Results:
- G6W oligomers exhibit strong affinity for unsaturated phospholipids, particularly those with 16-carbon alkyl chains.
- Molecular dynamics simulations show tight binding of these phospholipids within G6W's hydrophobic cavity.
- This selective binding is unique to G6W, with other amyloid oligomers showing no significant affinity.
Conclusions:
- G6W oligomers disrupt lipid homeostasis through selective protein-ligand interactions, not membrane perforation.
- This selective binding offers a new perspective on AO toxicity mechanisms.
- Potential toxic mechanisms include the formation of novel AO-lipid structures or impaired lipid transport.
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