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

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

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MDPI and ACS Style

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. https://doi.org/10.3390/ijms20143462

AMA Style

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. International Journal of Molecular Sciences. 2019; 20(14):3462. https://doi.org/10.3390/ijms20143462

Chicago/Turabian Style

Pavlin, Matic, Zena Qasem, Hila Sameach, Lada Gevorkyan-Airapetov, Ida Ritacco, Sharon Ruthstein, and Alessandra Magistrato. 2019. "Unraveling the Impact of Cysteine-to-Serine Mutations on the Structural and Functional Properties of Cu(I)-Binding Proteins" International Journal of Molecular Sciences 20, no. 14: 3462. https://doi.org/10.3390/ijms20143462

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

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