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The C291R Tau variant forms different types of protofibrils
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Karikari, Thomas K., Thomas, Rachel and Moffat, Kevin G. (2020) The C291R Tau variant forms different types of protofibrils. Frontiers in Molecular Neuroscience, 13 . 39. doi:10.3389/fnmol.2020.00039 ISSN 1662-5099.
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Official URL: https://doi.org/10.3389/fnmol.2020.00039
Abstract
Mutations in the MAPT gene can lead to disease-associated variants of tau. However, the pathological mechanisms behind these genetic tauopathies are poorly understood. Here, we characterized the aggregation stages and conformational changes of tau C291R, a recently described MAPT mutation with potential pathogenic functions. The C291R variant of the tau four-repeat domain (tau-K18; a functional fragment with increased aggregation propensity compared with the full-length protein), aggregated into a mix of granular oligomers, amorphous and annular pore-like aggregates, in native-state and heparin-treated reactions as observed using atomic force microscopy (AFM) and negative-stained electron microscopy. On extended incubation in the native-state, tau-K18 C291R oligomers, unlike wild type (WT) tau-K18, aggregated to form protofibrils of four different phenotypes: (1) spherical annular; (2) spherical annular encapsulating granular oligomers; (3) ring-like annular but non-spherical; and (4) linear protofibrils. The ring-like tau-K18 C291R aggregates shared key properties of annular protofibrils previously described for other amyloidogenic proteins, in addition to two unique features: irregular/non-spherical-shaped annular protofibrils, and spherical protofibrils encapsulating granular oligomers. Tau-K18 C291R monomers had a circular dichroism (CD) peak at ~210 nm compared with ~199 nm for tau-K18 WT. These data suggest mutation-enhanced β-sheet propensity. Together, we describe the characterization of tau-K18 C291R, the first genetic mutation substituting a cysteine residue. The aggregation mechanism of tau-K18 C291R appears to involve β-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures.
| Item Type: | Journal Article | |||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QH Natural history Q Science > QP Physiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||
| SWORD Depositor: | Library Publications Router | |||||||||
| Library of Congress Subject Headings (LCSH): | Microtubules, Tubulins, Proteins, Mutation (Biology), Nervous system -- Degeneration, Atomic force microscopy, Transmission electron microscopy | |||||||||
| Journal or Publication Title: | Frontiers in Molecular Neuroscience | |||||||||
| Publisher: | Frontiers Media S.A. | |||||||||
| ISSN: | 1662-5099 | |||||||||
| Official Date: | 18 March 2020 | |||||||||
| Dates: |
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| Volume: | 13 | |||||||||
| Article Number: | 39 | |||||||||
| DOI: | 10.3389/fnmol.2020.00039 | |||||||||
| Status: | Peer Reviewed | |||||||||
| Publication Status: | Published | |||||||||
| Reuse Statement (publisher, data, author rights): | ** From Frontiers via Jisc Publications Router ** History: received 17-12-2019; collection 2020; accepted 27-02-2020; epub 18-03-2020. ** Licence for this article: http://creativecommons.org/licenses/by/4.0/ | |||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||
| Date of first compliant deposit: | 14 April 2020 | |||||||||
| Date of first compliant Open Access: | 14 April 2020 | |||||||||
| RIOXX Funder/Project Grant: |
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