Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation
Abstract Recent studies of tau proteins point to specific sites or motifs along the protein related to its misfolding and aggregation propensity, which is associated with neurodegenerative diseases of structure-dependent pathology. In this manuscript we employ topology and geometry to analyze the lo...
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Nature Portfolio
2025-03-01
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| Online Access: | https://doi.org/10.1038/s41598-025-93304-x |
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| author | Masumi Sugiyama Kenneth S. Kosik Eleni Panagiotou |
| author_facet | Masumi Sugiyama Kenneth S. Kosik Eleni Panagiotou |
| author_sort | Masumi Sugiyama |
| collection | DOAJ |
| description | Abstract Recent studies of tau proteins point to specific sites or motifs along the protein related to its misfolding and aggregation propensity, which is associated with neurodegenerative diseases of structure-dependent pathology. In this manuscript we employ topology and geometry to analyze the local structure of tau proteins obtained from the Protein Data Bank. Our results show that mathematical topology/geometry of cryo-EM structures alone identify the PGGG motifs, and the PHF6(*) motifs as sites of interest and reveal a geometrical hierarchy of the PGGG motifs that differs for 3R+4R and 4R tauopathies. By employing the Local Topological Free Energy (LTE), we find that progressive supranuclear palsy (PSP) and globular glial tauopathy (GGT) have the highest LTE values around residues 302–305, which are inside the jR2R3 peptide and in the vicinity of the 301 site, experimentally associated with aggregation. By extending the LTE definition to estimate a global topological free energy, we find that the jR2R3 peptide of PSP and GGT, has in fact the lowest global topological free energy among other tauopathies. These results point to a possible correlation between the global topological free energy of parts of the protein and the LTE of specific sites. |
| format | Article |
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| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-13f31f260cd64ab8a819d96909b58db32025-08-20T02:10:13ZengNature PortfolioScientific Reports2045-23222025-03-0115111210.1038/s41598-025-93304-xGeometry based prediction of tau protein sites and motifs associated with misfolding and aggregationMasumi Sugiyama0Kenneth S. Kosik1Eleni Panagiotou2Department of Mathematics, University of Tennessee at ChattanoogaNeuroscience Research Institute and Department of Molecular, Cellular, and Developmental Biology, University of California Santa BarbaraSchool of Mathematical and Statistical Sciences, Arizona State UniversityAbstract Recent studies of tau proteins point to specific sites or motifs along the protein related to its misfolding and aggregation propensity, which is associated with neurodegenerative diseases of structure-dependent pathology. In this manuscript we employ topology and geometry to analyze the local structure of tau proteins obtained from the Protein Data Bank. Our results show that mathematical topology/geometry of cryo-EM structures alone identify the PGGG motifs, and the PHF6(*) motifs as sites of interest and reveal a geometrical hierarchy of the PGGG motifs that differs for 3R+4R and 4R tauopathies. By employing the Local Topological Free Energy (LTE), we find that progressive supranuclear palsy (PSP) and globular glial tauopathy (GGT) have the highest LTE values around residues 302–305, which are inside the jR2R3 peptide and in the vicinity of the 301 site, experimentally associated with aggregation. By extending the LTE definition to estimate a global topological free energy, we find that the jR2R3 peptide of PSP and GGT, has in fact the lowest global topological free energy among other tauopathies. These results point to a possible correlation between the global topological free energy of parts of the protein and the LTE of specific sites.https://doi.org/10.1038/s41598-025-93304-xNeurodegenerative diseaseTau proteinStructureTopologyGeometryAggregation |
| spellingShingle | Masumi Sugiyama Kenneth S. Kosik Eleni Panagiotou Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation Scientific Reports Neurodegenerative disease Tau protein Structure Topology Geometry Aggregation |
| title | Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation |
| title_full | Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation |
| title_fullStr | Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation |
| title_full_unstemmed | Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation |
| title_short | Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation |
| title_sort | geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation |
| topic | Neurodegenerative disease Tau protein Structure Topology Geometry Aggregation |
| url | https://doi.org/10.1038/s41598-025-93304-x |
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