Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation
Abstract N- and C-terminal α-synuclein (α-syn) truncations are prevalent in Parkinson’s disease. Effects of the N- and C-terminal residues on α-syn aggregation and fibril propagation are distinct, where the N-terminus dictates fibril structure. Here, the majority of α-syn truncations are assigned by...
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| Format: | Article |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58899-9 |
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| author | Ryan P. McGlinchey Sashary Ramos Emilios K. Dimitriadis C. Blake Wilson Jennifer C. Lee |
| author_facet | Ryan P. McGlinchey Sashary Ramos Emilios K. Dimitriadis C. Blake Wilson Jennifer C. Lee |
| author_sort | Ryan P. McGlinchey |
| collection | DOAJ |
| description | Abstract N- and C-terminal α-synuclein (α-syn) truncations are prevalent in Parkinson’s disease. Effects of the N- and C-terminal residues on α-syn aggregation and fibril propagation are distinct, where the N-terminus dictates fibril structure. Here, the majority of α-syn truncations are assigned by intact mass spectrometry to lysosomal activity. To delineate essential charged residues in fibril formation, we selected an N-terminal truncation (66–140) that is generated solely from soluble α-syn by asparagine endopeptidase. Ala-substitutions at K80 and E83 impact aggregation kinetics, revealing their vital roles in defining fibril polymorphism. K80, E83, and K97 are identified to be critical for fibril elongation. Based on solid-state NMR, mutational and Raman studies, and molecular dynamics simulations, a E83–K97 salt bridge is proposed. Finally, participation of C-terminal Lys residues in the full-length α-syn fibril assembly process is also shown, highlighting that individual residues can be targeted for therapeutic intervention. |
| format | Article |
| id | doaj-art-77d7d3fe3db44f4ca2001eae8d9636c1 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-77d7d3fe3db44f4ca2001eae8d9636c12025-08-20T02:30:26ZengNature PortfolioNature Communications2041-17232025-04-0116111510.1038/s41467-025-58899-9Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncationRyan P. McGlinchey0Sashary Ramos1Emilios K. Dimitriadis2C. Blake Wilson3Jennifer C. Lee4Laboratory of Protein Conformation and Dynamics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of HealthLaboratory of Protein Conformation and Dynamics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of HealthBiomedical Engineering and Physical Science Shared Resource Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of HealthLaboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthLaboratory of Protein Conformation and Dynamics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of HealthAbstract N- and C-terminal α-synuclein (α-syn) truncations are prevalent in Parkinson’s disease. Effects of the N- and C-terminal residues on α-syn aggregation and fibril propagation are distinct, where the N-terminus dictates fibril structure. Here, the majority of α-syn truncations are assigned by intact mass spectrometry to lysosomal activity. To delineate essential charged residues in fibril formation, we selected an N-terminal truncation (66–140) that is generated solely from soluble α-syn by asparagine endopeptidase. Ala-substitutions at K80 and E83 impact aggregation kinetics, revealing their vital roles in defining fibril polymorphism. K80, E83, and K97 are identified to be critical for fibril elongation. Based on solid-state NMR, mutational and Raman studies, and molecular dynamics simulations, a E83–K97 salt bridge is proposed. Finally, participation of C-terminal Lys residues in the full-length α-syn fibril assembly process is also shown, highlighting that individual residues can be targeted for therapeutic intervention.https://doi.org/10.1038/s41467-025-58899-9 |
| spellingShingle | Ryan P. McGlinchey Sashary Ramos Emilios K. Dimitriadis C. Blake Wilson Jennifer C. Lee Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation Nature Communications |
| title | Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation |
| title_full | Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation |
| title_fullStr | Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation |
| title_full_unstemmed | Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation |
| title_short | Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation |
| title_sort | defining essential charged residues in fibril formation of a lysosomal derived n terminal α synuclein truncation |
| url | https://doi.org/10.1038/s41467-025-58899-9 |
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