Destabilisation of the structure of transthyretin is driven by Ca2.

Tetrameric transthyretin (TTR) transports thyroid hormones and retinol in plasma and cerebrospinal fluid and performs protective functions under stress conditions. Ageing and mutations result in TTR destabilisation and the formation of the amyloid deposits that dysregulate Ca2+ homeostasis. Our aim was to determine whether Ca2+ affects the structural stability of TTR. We show, using multiple techniques, that Ca2+ does not induce prevalent TTR dissociation and/or oligomerisation. However, in the presence of Ca2+, TTR exhibits altered conformational flexibility and different interactions with the solvent molecules. These structural changes lead to the formation of the sub-populations of non-native TTR conformers and to the destabilisation of the structure of TTR. Moreover, the sub-population of TTR molecules undergoes fragmentation that is augmented by Ca2+. We postulate that Ca2+ constitutes the structural and functional switch between the native and non-native forms of TTR, and therefore tip the balance towards age-dependent pathological calcification. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Elżbieta Wieczorek, Sylwia Kędracka-Krok, Dominika Bystranowska, Maciej Ptak, Karolina Wiak, Zofia Wygralak, Urszula Jankowska, Andrzej Ożyhar. Destabilisation of the structure of transthyretin is driven by Ca2. International journal of biological macromolecules. 2021 Jan 01;166:409-423

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PMID: 33129902

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