Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s
The disruption of cell membranes by tau and amylin oligomers is linked to amyloid diseases such as Alzheimer’s and diabetes, respectively. The recent studies suggest that misfolded tau and amylin can form neurotoxic hetero-oligomers that are structurally different from homo-oligomers. However, the m...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Macromol |
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| Online Access: | https://www.mdpi.com/2673-6209/3/4/46 |
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| author | Natalia Santos Luthary Segura Amber Lewis Thuong Pham Kwan H. Cheng |
| author_facet | Natalia Santos Luthary Segura Amber Lewis Thuong Pham Kwan H. Cheng |
| author_sort | Natalia Santos |
| collection | DOAJ |
| description | The disruption of cell membranes by tau and amylin oligomers is linked to amyloid diseases such as Alzheimer’s and diabetes, respectively. The recent studies suggest that misfolded tau and amylin can form neurotoxic hetero-oligomers that are structurally different from homo-oligomers. However, the molecular interactions of these hetero-oligomers with the neuronal membranes remain unclear. Using MD simulations, we have investigated the binding behaviors, membrane disruption, and protein folding of hetero-oligomers on a raft membrane containing phase-separated lipid nanodomains like those found in neurons. We discovered that the hetero-oligomers bind to the liquid-order and liquid-disorder phase boundaries of the raft membrane. The major lipid-binding sites of these interactions include the L16 and I26 residues of amylin and the <i>N</i>-terminal of tau. Strong disruptions of the raft domain size by the hetero-tetramer were detected. Furthermore, the hetero-dimer disrupted the saturated phospholipid orientational order to a greater extent than the individual tau or amylin monomer. In addition, the constituent tau more strongly promoted the alpha-helix to the beta-sheet transition of the constituent amylin within the hetero-dimer when compared with the amylin monomer alone. Our results provide new molecular insights into understanding the neurotoxicity of the hetero-oligomers associated with the cross-talk between amyloid diseases. |
| first_indexed | 2024-03-08T20:34:30Z |
| format | Article |
| id | doaj.art-0b9657e898704dc08cdc21aa9d7c864d |
| institution | Directory Open Access Journal |
| issn | 2673-6209 |
| language | English |
| last_indexed | 2024-03-08T20:34:30Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Macromol |
| spelling | doaj.art-0b9657e898704dc08cdc21aa9d7c864d2023-12-22T14:22:04ZengMDPI AGMacromol2673-62092023-12-013480582710.3390/macromol3040046Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’sNatalia Santos0Luthary Segura1Amber Lewis2Thuong Pham3Kwan H. Cheng4Neuroscience Department, Trinity University, San Antonio, TX 78212, USANeuroscience Department, Trinity University, San Antonio, TX 78212, USANeuroscience Department, Trinity University, San Antonio, TX 78212, USAPhysics Department, Trinity University, San Antonio, TX 78212, USANeuroscience Department, Trinity University, San Antonio, TX 78212, USAThe disruption of cell membranes by tau and amylin oligomers is linked to amyloid diseases such as Alzheimer’s and diabetes, respectively. The recent studies suggest that misfolded tau and amylin can form neurotoxic hetero-oligomers that are structurally different from homo-oligomers. However, the molecular interactions of these hetero-oligomers with the neuronal membranes remain unclear. Using MD simulations, we have investigated the binding behaviors, membrane disruption, and protein folding of hetero-oligomers on a raft membrane containing phase-separated lipid nanodomains like those found in neurons. We discovered that the hetero-oligomers bind to the liquid-order and liquid-disorder phase boundaries of the raft membrane. The major lipid-binding sites of these interactions include the L16 and I26 residues of amylin and the <i>N</i>-terminal of tau. Strong disruptions of the raft domain size by the hetero-tetramer were detected. Furthermore, the hetero-dimer disrupted the saturated phospholipid orientational order to a greater extent than the individual tau or amylin monomer. In addition, the constituent tau more strongly promoted the alpha-helix to the beta-sheet transition of the constituent amylin within the hetero-dimer when compared with the amylin monomer alone. Our results provide new molecular insights into understanding the neurotoxicity of the hetero-oligomers associated with the cross-talk between amyloid diseases.https://www.mdpi.com/2673-6209/3/4/46amyloid aggregatesprotein foldingmolecular dynamicslipid raftsprotein misfolding diseaseAlzheimer’s |
| spellingShingle | Natalia Santos Luthary Segura Amber Lewis Thuong Pham Kwan H. Cheng Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s Macromol amyloid aggregates protein folding molecular dynamics lipid rafts protein misfolding disease Alzheimer’s |
| title | Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s |
| title_full | Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s |
| title_fullStr | Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s |
| title_full_unstemmed | Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s |
| title_short | Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s |
| title_sort | molecular mechanisms of protein lipid interactions and protein folding of heterogeneous amylin and tau oligomers on lipid nanodomains that link to alzheimer s |
| topic | amyloid aggregates protein folding molecular dynamics lipid rafts protein misfolding disease Alzheimer’s |
| url | https://www.mdpi.com/2673-6209/3/4/46 |
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