Article
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An Overlooked Hepcidin-cadmium Connection
Version 1
: Received: 13 October 2022 / Approved: 28 October 2022 / Online: 28 October 2022 (13:00:05 CEST)
A peer-reviewed article of this Preprint also exists.
Płonka, D.; Wiśniewska, M.D.; Peris-Díaz, M.D.; Krężel, A.; Bonna, A.M.; Bal, W. An Overlooked Hepcidin–Cadmium Connection. Int. J. Mol. Sci. 2022, 23, 15483. Płonka, D.; Wiśniewska, M.D.; Peris-Díaz, M.D.; Krężel, A.; Bonna, A.M.; Bal, W. An Overlooked Hepcidin–Cadmium Connection. Int. J. Mol. Sci. 2022, 23, 15483.
Abstract
Hepcidin (DTHFPICIFCCGCCHRSKCGMCCKT), an iron regulatory hormone is a 25 amino acid peptide with 4 intramolecular disulfide bonds, circulating in blood. Its hormonal activity is indirect and consists of marking ferroportin-1 (an iron exporter) for degradation. Hepcidin biosynthesis involves N-terminally extended precursors prepro-hepcidin and pro-hepcidin, processed by peptidases to the final 25-peptide form. A sequence-specific formation of disulfide bonds and export of the oxidized peptide to the bloodstream follows. In this study we considered the fact that prior to export, reduced hepcidin may function as an octathiol ligand bearing some resemblance to the N-terminal part of α-domain of metallothioneins. Consequently, we studied its ability to bind Zn(II) and Cd(II) ions using the original peptide and a model for prohepcidin, extended N-terminally with a stretch of five arginine residues (5R-hepcidin). We found that both form equivalent mononuclear complexes with two Zn(II) or Cd(II) ions saturating all eight Cys residues. The average affinity at pH 7.4, determined from pH-metric spectroscopic titrations, is 1010.1 M-1 for Zn(II) ions, the Cd(II) ions bind with affinities of 1015.2 M-1 and 1014.1 M-1. Using mass spectrometry and 5R-hepcidin we demonstrated that hepcidin can compete for Cd(II) ions with metallothionein-2, a cellular cadmium target. These studied empowered us to conclude that hepcidin binds Zn(II) and Cd(II) sufficiently strongly to participate in zinc physiology and cadmium toxicity under intracellular conditions.
Keywords
Hepcidin; prohepcidin; cadmium; affinity constant; metallothionein; MT2A
Subject
Biology and Life Sciences, Biophysics
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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