Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments
Abstract Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer’s disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss....
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38537-y |
| _version_ | 1797801363914096640 |
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| author | Gregory E. Merz Matthew J. Chalkley Sophia K. Tan Eric Tse Joanne Lee Stanley B. Prusiner Nick A. Paras William F. DeGrado Daniel R. Southworth |
| author_facet | Gregory E. Merz Matthew J. Chalkley Sophia K. Tan Eric Tse Joanne Lee Stanley B. Prusiner Nick A. Paras William F. DeGrado Daniel R. Southworth |
| author_sort | Gregory E. Merz |
| collection | DOAJ |
| description | Abstract Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer’s disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo–electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule–protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases. |
| first_indexed | 2024-03-13T04:49:20Z |
| format | Article |
| id | doaj.art-4d453a94c2d04d8b84481f4520c5fd9e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T04:49:20Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-4d453a94c2d04d8b84481f4520c5fd9e2023-06-18T11:18:52ZengNature PortfolioNature Communications2041-17232023-05-0114111110.1038/s41467-023-38537-yStacked binding of a PET ligand to Alzheimer’s tau paired helical filamentsGregory E. Merz0Matthew J. Chalkley1Sophia K. Tan2Eric Tse3Joanne Lee4Stanley B. Prusiner5Nick A. Paras6William F. DeGrado7Daniel R. Southworth8Institute for Neurodegenerative Diseases, University of California San FranciscoDepartment of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San FranciscoDepartment of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San FranciscoInstitute for Neurodegenerative Diseases, University of California San FranciscoInstitute for Neurodegenerative Diseases, University of California San FranciscoInstitute for Neurodegenerative Diseases, University of California San FranciscoInstitute for Neurodegenerative Diseases, University of California San FranciscoInstitute for Neurodegenerative Diseases, University of California San FranciscoInstitute for Neurodegenerative Diseases, University of California San FranciscoAbstract Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer’s disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo–electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule–protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.https://doi.org/10.1038/s41467-023-38537-y |
| spellingShingle | Gregory E. Merz Matthew J. Chalkley Sophia K. Tan Eric Tse Joanne Lee Stanley B. Prusiner Nick A. Paras William F. DeGrado Daniel R. Southworth Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments Nature Communications |
| title | Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments |
| title_full | Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments |
| title_fullStr | Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments |
| title_full_unstemmed | Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments |
| title_short | Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments |
| title_sort | stacked binding of a pet ligand to alzheimer s tau paired helical filaments |
| url | https://doi.org/10.1038/s41467-023-38537-y |
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