Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations
The self-aggregation of tau, a microtubule-binding protein, has been linked to the onset of Alzheimer’s Disease. Recent studies indicate that the disordered tau aggregates, or oligomers, are more toxic than the ordered fibrils found in the intracellular neurofibrillary tangles of tau. At present, de...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Membranes |
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| Online Access: | https://www.mdpi.com/2077-0375/12/11/1098 |
| _version_ | 1797467349324922880 |
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| author | Kwan H. Cheng Angela Graf Amber Lewis Thuong Pham Aakriti Acharya |
| author_facet | Kwan H. Cheng Angela Graf Amber Lewis Thuong Pham Aakriti Acharya |
| author_sort | Kwan H. Cheng |
| collection | DOAJ |
| description | The self-aggregation of tau, a microtubule-binding protein, has been linked to the onset of Alzheimer’s Disease. Recent studies indicate that the disordered tau aggregates, or oligomers, are more toxic than the ordered fibrils found in the intracellular neurofibrillary tangles of tau. At present, details of tau oligomer interactions with lipid rafts, a model of neuronal membranes, are not known. Using molecular dynamics simulations, the lipid-binding events, membrane-damage, and protein folding of tau oligomers on various lipid raft surfaces were investigated. Tau oligomers preferred to bind to the boundary domains (Lod) created by the coexisting liquid-ordered (Lo) and liquid-disordered (Ld) domains in the lipid rafts. Additionally, stronger binding of tau oligomers to the ganglioside (GM1) and phosphatidylserine (PS) domains, and subsequent protein-induced lipid chain order disruption and beta-sheet formation were detected. Our results suggest that GM1 and PS domains, located exclusively in the outer and inner leaflets, respectively, of the neuronal membranes, are specific membrane domain targets, whereas the Lod domains are non-specific targets, of tau oligomers binding to neurons. The molecular details of these specific and non-specific tau bindings to lipid rafts may provide new insights into understanding membrane-associated tauopathies leading to Alzheimer’s Disease. |
| first_indexed | 2024-03-09T18:51:24Z |
| format | Article |
| id | doaj.art-ef5b02faf49c4440aa865da8d341bcf8 |
| institution | Directory Open Access Journal |
| issn | 2077-0375 |
| language | English |
| last_indexed | 2024-03-09T18:51:24Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Membranes |
| spelling | doaj.art-ef5b02faf49c4440aa865da8d341bcf82023-11-24T05:49:05ZengMDPI AGMembranes2077-03752022-11-011211109810.3390/membranes12111098Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics SimulationsKwan H. Cheng0Angela Graf1Amber Lewis2Thuong Pham3Aakriti Acharya4Neuroscience Department, Trinity University, San Antonio, TX 78212, USAPhysics Department, Trinity University, San Antonio, TX 78212, USANeuroscience Department, Trinity University, San Antonio, TX 78212, USAPhysics Department, Trinity University, San Antonio, TX 78212, USAPhysics Department, Trinity University, San Antonio, TX 78212, USAThe self-aggregation of tau, a microtubule-binding protein, has been linked to the onset of Alzheimer’s Disease. Recent studies indicate that the disordered tau aggregates, or oligomers, are more toxic than the ordered fibrils found in the intracellular neurofibrillary tangles of tau. At present, details of tau oligomer interactions with lipid rafts, a model of neuronal membranes, are not known. Using molecular dynamics simulations, the lipid-binding events, membrane-damage, and protein folding of tau oligomers on various lipid raft surfaces were investigated. Tau oligomers preferred to bind to the boundary domains (Lod) created by the coexisting liquid-ordered (Lo) and liquid-disordered (Ld) domains in the lipid rafts. Additionally, stronger binding of tau oligomers to the ganglioside (GM1) and phosphatidylserine (PS) domains, and subsequent protein-induced lipid chain order disruption and beta-sheet formation were detected. Our results suggest that GM1 and PS domains, located exclusively in the outer and inner leaflets, respectively, of the neuronal membranes, are specific membrane domain targets, whereas the Lod domains are non-specific targets, of tau oligomers binding to neurons. The molecular details of these specific and non-specific tau bindings to lipid rafts may provide new insights into understanding membrane-associated tauopathies leading to Alzheimer’s Disease.https://www.mdpi.com/2077-0375/12/11/1098amyloidogenic proteinprotein aggregationneurodegenerative diseasesphase-separated lipid bilayerneuronal membranesMD simulations |
| spellingShingle | Kwan H. Cheng Angela Graf Amber Lewis Thuong Pham Aakriti Acharya Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations Membranes amyloidogenic protein protein aggregation neurodegenerative diseases phase-separated lipid bilayer neuronal membranes MD simulations |
| title | Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations |
| title_full | Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations |
| title_fullStr | Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations |
| title_full_unstemmed | Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations |
| title_short | Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations |
| title_sort | exploring membrane binding targets of disordered human tau aggregates on lipid rafts using multiscale molecular dynamics simulations |
| topic | amyloidogenic protein protein aggregation neurodegenerative diseases phase-separated lipid bilayer neuronal membranes MD simulations |
| url | https://www.mdpi.com/2077-0375/12/11/1098 |
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