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.