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- W2040995211 abstract "Huntington's disease (HD) is a genetic neurological disorder linked to the insertion of repeats of glutamine (Q) in the protein huntingtin. The increase in the number of Q results in polyglutamine (polyQ) expansions which self-associate to form aggregates. Significantly, there is a strong correlation between the age of onset in HD and the length of polyQ expansions, with postmortem examinations of HD patients identifying large inclusions in the brain. While polyQ aggregation has been the subject of intense studies, very little is known about the structural architecture of individual polyQ chains. An understanding of the molecular properties of polyQ chains is a necessary first step in building a framework to characterize polyQ expansion diseases. Here we demonstrate a single molecule force-clamp technique that directly probes the properties of polyQ. We have constructed polyQ constructs of varying length, namely Q15, Q25, Q50, Q75. Importantly, this length range spans the region where normal polyQ and diseased polyQ expansions have been observed. Each polyQ construct is flanked by the I27 titin module, providing a clear mechanical fingerprint of the molecule being pulled. Remarkably, under the application of force no extension is observed for all lengths of polyQ. We show this is in direct contrast with the random coil protein PEVK of titin which readily extends under force. Our measurements suggest that polyQ form highly stable mechanical structures. We test this hypothesis by disrupting polyQ with insertions of proline residues. Strikingly, upon interruption with prolines the polyQ constructs readily extend under force. These novel experiments provide the first glimpse of the molecular architecture of polyQ expansions, suggesting these structures are mechanically very stable. Such strong structures would be difficult to unravel and degrade in vivo, resulting in polyQ build-up and subsequent aggregation." @default.
- W2040995211 created "2016-06-24" @default.
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- W2040995211 date "2009-02-01" @default.
- W2040995211 modified "2023-09-29" @default.
- W2040995211 title "Extreme Mechanical Stability In Polyglutamine Chains Identified Using Single Molecule Force-clamp Spectroscopy" @default.
- W2040995211 doi "https://doi.org/10.1016/j.bpj.2008.12.1596" @default.
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