Summary: | Transthyretin (TTR) is a plasma homotetrameric protein that transports thyroxine and retinol. TTR itself, under pathological conditions, dissociates into partially unfolded monomers that aggregate and form fibrils. Metal ions such as Zn<sup>2+</sup>, Cu<sup>2+</sup>, Fe<sup>2+</sup>, Mn<sup>2+</sup> and Ca<sup>2+</sup> play a controversial role in the TTR amyloidogenic pathway. TTR is also present in cerebrospinal fluid (CSF), where it behaves as one of the major Aβ-binding-proteins. The interaction between TTR and Aβ is stronger in the presence of high concentrations of Cu<sup>2+</sup>. Crystals of TTR, soaked in solutions of physiological metals such as Cu<sup>2+</sup> and Fe<sup>2+</sup>, but not Mn<sup>2+</sup>, Zn<sup>2+</sup>, Fe<sup>3+</sup>, Al<sup>3+</sup>, Ni<sup>2+</sup>, revealed an unusual conformational change. Here, we investigate the effects that physiological metals have on TTR, in order to understand if metals can induce a specific and active conformation of TTR that guides its Aβ-scavenging role. The capability of certain metals to induce and accelerate its amyloidogenic process is also discussed.
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