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Open AccessArticle

Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins

1
CNR-IOM at SISSA, via Bonomea 265, 34135 Trieste, Italy
2
Department of Chemistry, Faculty of Exact Sciences, Bar Ilan University, Ramat-Gan 5290002, Israel
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(14), 3462; https://doi.org/10.3390/ijms20143462
Received: 20 June 2019 / Revised: 9 July 2019 / Accepted: 11 July 2019 / Published: 14 July 2019
Appropriate maintenance of Cu(I) homeostasis is an essential requirement for proper cell function because its misregulation induces the onset of major human diseases and mortality. For this reason, several research efforts have been devoted to dissecting the inner working mechanism of Cu(I)-binding proteins and transporters. A commonly adopted strategy relies on mutations of cysteine residues, for which Cu(I) has an exquisite complementarity, to serines. Nevertheless, in spite of the similarity between these two amino acids, the structural and functional impact of serine mutations on Cu(I)-binding biomolecules remains unclear. Here, we applied various biochemical and biophysical methods, together with all-atom simulations, to investigate the effect of these mutations on the stability, structure, and aggregation propensity of Cu(I)-binding proteins, as well as their interaction with specific partner proteins. Among Cu(I)-binding biomolecules, we focused on the eukaryotic Atox1-ATP7B system, and the prokaryotic CueR metalloregulator. Our results reveal that proteins containing cysteine-to-serine mutations can still bind Cu(I) ions; however, this alters their stability and aggregation propensity. These results contribute to deciphering the critical biological principles underlying the regulatory mechanism of the in-cell Cu(I) concentration, and provide a basis for interpreting future studies that will take advantage of cysteine-to-serine mutations in Cu(I)-binding systems. View Full-Text
Keywords: copper metabolism; serine mutations; Cu(I) affinity; CueR; Atox1; ATP7B; EPR; molecular dynamics; QM/MM copper metabolism; serine mutations; Cu(I) affinity; CueR; Atox1; ATP7B; EPR; molecular dynamics; QM/MM
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Pavlin, M.; Qasem, Z.; Sameach, H.; Gevorkyan-Airapetov, L.; Ritacco, I.; Ruthstein, S.; Magistrato, A. Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins. Int. J. Mol. Sci. 2019, 20, 3462.

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