The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus
Huntington disease is a neurodegenerative disease characterized by a polymorphic tract of polyglutamine repeats in exon 1 of the huntingtin protein, which is thought to be responsible for protein aggregation and neuronal death. The polyglutamine tract is preceded by a 17-residue sequence that is int...
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2019.00095/full |
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| author | Havva Yalinca Charlotte Julie Caroline Gehin Vladimiras Oleinikovas Hilal A. Lashuel Francesco Luigi Gervasio Francesco Luigi Gervasio Annalisa Pastore |
| author_facet | Havva Yalinca Charlotte Julie Caroline Gehin Vladimiras Oleinikovas Hilal A. Lashuel Francesco Luigi Gervasio Francesco Luigi Gervasio Annalisa Pastore |
| author_sort | Havva Yalinca |
| collection | DOAJ |
| description | Huntington disease is a neurodegenerative disease characterized by a polymorphic tract of polyglutamine repeats in exon 1 of the huntingtin protein, which is thought to be responsible for protein aggregation and neuronal death. The polyglutamine tract is preceded by a 17-residue sequence that is intrinsically disordered. This region is subject to phosphorylation, acetylation and other post-translational modifications in vivo, which modulate its secondary structure, aggregation and, subcellular localization. We used Molecular Dynamics simulations with a novel Hamiltonian-replica-exchange-based enhanced sampling method, SWISH, and an optimal combination of water and protein force fields to study the effects of phosphorylation and acetylation as well as cross-talk between these modifications on the huntingtin N-terminus. The simulations, validated by circular dichroism, were used to formulate a mechanism by which the modifications influence helical conformations. Our findings have implications for understanding the structural basis underlying the effect of PTMs in the aggregation and cellular properties of huntingtin. |
| first_indexed | 2024-12-20T07:07:30Z |
| format | Article |
| id | doaj.art-f74da572641947ba92c8817e52ee62e5 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-20T07:07:30Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-f74da572641947ba92c8817e52ee62e52022-12-21T19:49:01ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2019-10-01610.3389/fmolb.2019.00095481607The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-TerminusHavva Yalinca0Charlotte Julie Caroline Gehin1Vladimiras Oleinikovas2Hilal A. Lashuel3Francesco Luigi Gervasio4Francesco Luigi Gervasio5Annalisa Pastore6Department of Chemistry, University College London, London, United KingdomLaboratory of Molecular and Chemical Biology of Neurodegeneration, Faculty of Life Sciences, Brain Mind Institute, EPFL, Lausanne, SwitzerlandDepartment of Chemistry, University College London, London, United KingdomLaboratory of Molecular and Chemical Biology of Neurodegeneration, Faculty of Life Sciences, Brain Mind Institute, EPFL, Lausanne, SwitzerlandDepartment of Chemistry, University College London, London, United KingdomResearch Department of Structural and Molecular Biology, University College London, London, United KingdomKing's College London, London, United KingdomHuntington disease is a neurodegenerative disease characterized by a polymorphic tract of polyglutamine repeats in exon 1 of the huntingtin protein, which is thought to be responsible for protein aggregation and neuronal death. The polyglutamine tract is preceded by a 17-residue sequence that is intrinsically disordered. This region is subject to phosphorylation, acetylation and other post-translational modifications in vivo, which modulate its secondary structure, aggregation and, subcellular localization. We used Molecular Dynamics simulations with a novel Hamiltonian-replica-exchange-based enhanced sampling method, SWISH, and an optimal combination of water and protein force fields to study the effects of phosphorylation and acetylation as well as cross-talk between these modifications on the huntingtin N-terminus. The simulations, validated by circular dichroism, were used to formulate a mechanism by which the modifications influence helical conformations. Our findings have implications for understanding the structural basis underlying the effect of PTMs in the aggregation and cellular properties of huntingtin.https://www.frontiersin.org/article/10.3389/fmolb.2019.00095/fullHuntington's diseasemisfolding diseasemolecular dynamicspeptide foldingphosphorylationpost-translational modifications |
| spellingShingle | Havva Yalinca Charlotte Julie Caroline Gehin Vladimiras Oleinikovas Hilal A. Lashuel Francesco Luigi Gervasio Francesco Luigi Gervasio Annalisa Pastore The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus Frontiers in Molecular Biosciences Huntington's disease misfolding disease molecular dynamics peptide folding phosphorylation post-translational modifications |
| title | The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus |
| title_full | The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus |
| title_fullStr | The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus |
| title_full_unstemmed | The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus |
| title_short | The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus |
| title_sort | role of post translational modifications on the energy landscape of huntingtin n terminus |
| topic | Huntington's disease misfolding disease molecular dynamics peptide folding phosphorylation post-translational modifications |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2019.00095/full |
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