Effects of iron on the aggregation propensity of the N-terminal fibrillogenic polypeptide of human apolipoprotein A-I Article First Online: 05 April 2018 Received: 31 January 2018 Accepted: 03 April 2018 Abstract
Specific mutations in APOA1 gene lead to systemic, hereditary amyloidoses. In ApoA-I related amyloidosis involving the heart, amyloid deposits are mainly constituted by the 93-residue N-terminal region of the protein, here indicated as [1-93]ApoA-I. Oxidative stress is known to be an enhancing factor for protein aggregation. In healthy conditions, humans are able to counteract the formation and the effects of oxidative molecules. However, aging and atmospheric pollution increase the concentration of oxidative agents, such as metal ions. As the main effect of iron deregulation is proposed to be an increase in oxidative stress, we analysed the effects of iron on [1-93]ApoA-I aggregation. By using different biochemical approaches, we demonstrated that Fe(II) is able to reduce the formation of [1-93]ApoA-I fibrillar species, probably by stabilizing its monomeric form, whereas Fe(III) shows a positive effect on polypeptide fibrillogenesis. We hypothesize that, in healthy conditions, Fe(III) is reduced by the organism to Fe(II), thus inhibiting amyloid formation, whereas during ageing such protective mechanisms decline, thus exposing the organism to higher oxidative stress levels, which are also related to an increase in Fe(III). This alteration could contribute to the pathogenesis of amyloidosis.
Keywords Protein aggregation Conformational analysis ApoA-I Amyloidosis Iron Electronic supplementary material
The online version of this article (
) contains supplementary material, which is available to authorized users. https://doi.org/10.1007/s10534-018-0101-y Notes Acknowledgements
We thank Dr. Amanda Penco for helping in AFM analyses.
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