Pires, Ricardo H. and Saraiva, Maria J. and Damas, Ana M. and Kellermayer, Miklós (2016) Force spectroscopy reveals the presence of structurally modified dimers in transthyretin amyloid annular oligomers. JOURNAL OF MOLECULAR RECOGNITION, 30 (3). e2587. ISSN 0952-3499
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Abstract
Toxicity in amyloidogenic protein misfolding disorders is thought to involve intermediate states of aggregation associated with the formation of amyloid fibrils. Despite their relevance, the heterogeneity and transience of these oligomers have placed great barriers in our understanding of their structural properties. Among amyloid intermediates, annular oligomers or annular protofibrils have raised considerable interest because they may contribute to a mechanism of cellular toxicity via membrane permeation. Here we investigated, by using AFM force spectroscopy, the structural detail of amyloid annular oligomers from transthyretin (TTR), a protein involved in systemic and neurodegenerative amyloidogenic disorders. Manipulation was performed in situ, in the absence of molecular handles and using persistence length-fit values to select relevant curves. Force curves reveal the presence of dimers in TTR annular oligomers that unfold via a series of structural intermediates. This is in contrast with the manipulation of native TTR that was more often manipulated over length scales compatible with a TTR monomer and without unfolding intermediates. Imaging and force spectroscopy data suggest that dimers are formed by the assembly of monomers in a head-to-head orientation with a nonnative interface along their beta-strands. Furthermore, these dimers stack through nonnative contacts that may enhance the stability of the misfolded structure.
Item Type: | Article |
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Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3020 Biophysics / biofizika |
SWORD Depositor: | MTMT SWORD |
Depositing User: | MTMT SWORD |
Date Deposited: | 14 Feb 2017 14:37 |
Last Modified: | 01 Feb 2018 00:15 |
URI: | http://real.mtak.hu/id/eprint/48809 |
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