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The Scs disulfide reductase system cooperates with the metallochaperone CueP in Salmonella copper resistance.
J Biol Chem. 2019 11 01; 294(44):15876-15888.JB

Abstract

The human pathogen Salmonella enterica serovar Typhimurium (S Typhimurium) contains a complex disulfide bond (Dsb) catalytic machinery. This machinery encompasses multiple Dsb thiol-disulfide oxidoreductases that mediate oxidative protein folding and a less-characterized suppressor of copper sensitivity (scs) gene cluster, associated with increased tolerance to copper. To better understand the function of the Salmonella Scs system, here we characterized two of its key components, the membrane protein ScsB and the periplasmic protein ScsC. Our results revealed that these two proteins form a redox pair in which the electron transfer from the periplasmic domain of ScsB (n-ScsB) to ScsC is thermodynamically driven. We also demonstrate that the Scs reducing pathway remains separate from the Dsb oxidizing pathways and thereby avoids futile redox cycles. Additionally, we provide new insight into the molecular mechanism underlying Scs-mediated copper tolerance in Salmonella We show that both ScsB and ScsC can bind toxic copper(I) with femtomolar affinities and transfer it to the periplasmic copper metallochaperone CueP. Our results indicate that the Salmonella Scs machinery has evolved a dual mode of action, capable of transferring reducing power to the oxidizing periplasm and protecting against copper stress by cooperating with the cue regulon, a major copper resistance mechanism in Salmonella. Overall, these findings expand our understanding of the functional diversity of Dsb-like systems, ranging from those mediating oxidative folding of proteins required for infection to those contributing to defense mechanisms against oxidative stress and copper toxicity, critical traits for niche adaptation and survival.

Authors+Show Affiliations

Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3083, Australia.Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3083, Australia.Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3083, Australia.School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3083, Australia b.heras@latrobe.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31444272

Citation

Subedi, Pramod, et al. "The Scs Disulfide Reductase System Cooperates With the Metallochaperone CueP in Salmonella Copper Resistance." The Journal of Biological Chemistry, vol. 294, no. 44, 2019, pp. 15876-15888.
Subedi P, Paxman JJ, Wang G, et al. The Scs disulfide reductase system cooperates with the metallochaperone CueP in Salmonella copper resistance. J Biol Chem. 2019;294(44):15876-15888.
Subedi, P., Paxman, J. J., Wang, G., Ukuwela, A. A., Xiao, Z., & Heras, B. (2019). The Scs disulfide reductase system cooperates with the metallochaperone CueP in Salmonella copper resistance. The Journal of Biological Chemistry, 294(44), 15876-15888. https://doi.org/10.1074/jbc.RA119.010164
Subedi P, et al. The Scs Disulfide Reductase System Cooperates With the Metallochaperone CueP in Salmonella Copper Resistance. J Biol Chem. 2019 11 1;294(44):15876-15888. PubMed PMID: 31444272.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Scs disulfide reductase system cooperates with the metallochaperone CueP in Salmonella copper resistance. AU - Subedi,Pramod, AU - Paxman,Jason J, AU - Wang,Geqing, AU - Ukuwela,Ashwinie A, AU - Xiao,Zhiguang, AU - Heras,Begoña, Y1 - 2019/08/23/ PY - 2019/07/12/received PY - 2019/08/21/revised PY - 2019/8/25/pubmed PY - 2020/6/13/medline PY - 2019/8/25/entrez KW - Dsb proteins KW - Salmonella enterica KW - Scs proteins KW - bacterial copper resistance KW - copper KW - copper homeostasis KW - disulfide KW - disulfide catalysis KW - electron transfer KW - oxidation-reduction (redox) SP - 15876 EP - 15888 JF - The Journal of biological chemistry JO - J Biol Chem VL - 294 IS - 44 N2 - The human pathogen Salmonella enterica serovar Typhimurium (S Typhimurium) contains a complex disulfide bond (Dsb) catalytic machinery. This machinery encompasses multiple Dsb thiol-disulfide oxidoreductases that mediate oxidative protein folding and a less-characterized suppressor of copper sensitivity (scs) gene cluster, associated with increased tolerance to copper. To better understand the function of the Salmonella Scs system, here we characterized two of its key components, the membrane protein ScsB and the periplasmic protein ScsC. Our results revealed that these two proteins form a redox pair in which the electron transfer from the periplasmic domain of ScsB (n-ScsB) to ScsC is thermodynamically driven. We also demonstrate that the Scs reducing pathway remains separate from the Dsb oxidizing pathways and thereby avoids futile redox cycles. Additionally, we provide new insight into the molecular mechanism underlying Scs-mediated copper tolerance in Salmonella We show that both ScsB and ScsC can bind toxic copper(I) with femtomolar affinities and transfer it to the periplasmic copper metallochaperone CueP. Our results indicate that the Salmonella Scs machinery has evolved a dual mode of action, capable of transferring reducing power to the oxidizing periplasm and protecting against copper stress by cooperating with the cue regulon, a major copper resistance mechanism in Salmonella. Overall, these findings expand our understanding of the functional diversity of Dsb-like systems, ranging from those mediating oxidative folding of proteins required for infection to those contributing to defense mechanisms against oxidative stress and copper toxicity, critical traits for niche adaptation and survival. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/31444272/The_Scs_disulfide_reductase_system_cooperates_with_the_metallochaperone_CueP_in_Salmonella_copper_resistance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)30448-8 DB - PRIME DP - Unbound Medicine ER -