Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy
Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1–121), composed of two protofibrils that are connected via a densely-packed interface...
| Main Authors: | , , , , , , , , , , , , , , , |
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eLife Sciences Publications Ltd
2019-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/48907 |
| _version_ | 1811202709936668672 |
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| author | Ricardo Guerrero-Ferreira Nicholas MI Taylor Ana-Andreea Arteni Pratibha Kumari Daniel Mona Philippe Ringler Markus Britschgi Matthias E Lauer Ali Makky Joeri Verasdonck Roland Riek Ronald Melki Beat H Meier Anja Böckmann Luc Bousset Henning Stahlberg |
| author_facet | Ricardo Guerrero-Ferreira Nicholas MI Taylor Ana-Andreea Arteni Pratibha Kumari Daniel Mona Philippe Ringler Markus Britschgi Matthias E Lauer Ali Makky Joeri Verasdonck Roland Riek Ronald Melki Beat H Meier Anja Böckmann Luc Bousset Henning Stahlberg |
| author_sort | Ricardo Guerrero-Ferreira |
| collection | DOAJ |
| description | Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1–121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability. |
| first_indexed | 2024-04-12T02:44:14Z |
| format | Article |
| id | doaj.art-5511896652574ffdab1b13b67a01332c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:44:14Z |
| publishDate | 2019-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5511896652574ffdab1b13b67a01332c2022-12-22T03:51:15ZengeLife Sciences Publications LtdeLife2050-084X2019-12-01810.7554/eLife.48907Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopyRicardo Guerrero-Ferreira0https://orcid.org/0000-0002-3664-8277Nicholas MI Taylor1https://orcid.org/0000-0003-0761-4921Ana-Andreea Arteni2https://orcid.org/0000-0001-6462-905XPratibha Kumari3Daniel Mona4Philippe Ringler5https://orcid.org/0000-0003-4346-5089Markus Britschgi6https://orcid.org/0000-0001-6151-4257Matthias E Lauer7https://orcid.org/0000-0003-3252-8718Ali Makky8Joeri Verasdonck9Roland Riek10Ronald Melki11Beat H Meier12https://orcid.org/0000-0002-9107-4464Anja Böckmann13https://orcid.org/0000-0001-8149-7941Luc Bousset14Henning Stahlberg15https://orcid.org/0000-0002-1185-4592Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Basel, SwitzerlandStructural Biology of Molecular Machines Group, Protein Structure & Function Programme, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkInstitut de Biologie Intégrative de la Cellule (I2BC), CEA, CNRS, Université Paris Sud, Université Paris-Saclay, Gif-sur-Yvette, France; Institut Fancois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-Aux-Roses, FranceLaboratory of Physical Chemistry, ETH Zurich, Zurich, SwitzerlandRoche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Medicine Area, Neuroscience Discovery, Roche Innovation Center Basel, Basel, SwitzerlandCenter for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Basel, SwitzerlandRoche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Medicine Area, Neuroscience Discovery, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, Basel, SwitzerlandInstitut Galien Paris-Sud, CNRS, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, FranceLaboratory of Physical Chemistry, ETH Zurich, Zurich, SwitzerlandLaboratory of Physical Chemistry, ETH Zurich, Zurich, SwitzerlandInstitut Fancois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-Aux-Roses, FranceLaboratory of Physical Chemistry, ETH Zurich, Zurich, SwitzerlandMolecular Microbiology and Structural Biochemistry, Labex Ecofect, UMR 5086 CNRS, Université de Lyon, Lyon, FranceInstitut Fancois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-Aux-Roses, FranceCenter for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, University of Basel, Basel, SwitzerlandIntracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson’s disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1–121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50–57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.https://elifesciences.org/articles/48907Parkinson's diseasealpha-synucleincryo-EMstructural biologyneurodegeneration |
| spellingShingle | Ricardo Guerrero-Ferreira Nicholas MI Taylor Ana-Andreea Arteni Pratibha Kumari Daniel Mona Philippe Ringler Markus Britschgi Matthias E Lauer Ali Makky Joeri Verasdonck Roland Riek Ronald Melki Beat H Meier Anja Böckmann Luc Bousset Henning Stahlberg Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy eLife Parkinson's disease alpha-synuclein cryo-EM structural biology neurodegeneration |
| title | Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy |
| title_full | Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy |
| title_fullStr | Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy |
| title_full_unstemmed | Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy |
| title_short | Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy |
| title_sort | two new polymorphic structures of human full length alpha synuclein fibrils solved by cryo electron microscopy |
| topic | Parkinson's disease alpha-synuclein cryo-EM structural biology neurodegeneration |
| url | https://elifesciences.org/articles/48907 |
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