Hydrogen peroxide-dependent oxidation of ERK2 within its D-recruitment site alters its substrate selection

Authors

• Anthony E. Postiglione, North Carolina Agricultural and Technical State University
• Laquaundra L. Adams, North Carolina Agricultural and Technical State University
• Ese S. Ekhator, North Carolina Agricultural and Technical State University
• Anuoluwapo E. Odelade, North Carolina Agricultural and Technical State University
• Supriya Patwardhan, North Carolina Agricultural and Technical State University
• Meenal Chaudhari, North Carolina Agricultural and Technical State University
• Avery S. Pardue, North Carolina Agricultural and Technical State University
• Anjali Kumari, North Carolina Agricultural and Technical State University
• William A. LeFever, High Point University
• Olivia P. Tornow, High Point University
• Tamer S. Kaoud, The University of Texas at Austin
• Johnathan Neiswinger, Johns Hopkins School of Medicine
• Jun Seop Jeong, North Carolina Agricultural and Technical State University
• Derek Parsonage, Wake Forest University School of Medicine
• Kimberly J. Nelson, Wake Forest University School of Medicine
• Dukka KC, Michigan Technological UniversityFollow
• Cristina M. Furdui, Wake Forest University School of Medicine
• Heng Zhu, Johns Hopkins School of Medicine
• Andrew J. Wommack, High Point University
• Kevin N. Dalby, The University of Texas at Austin
• Ming Dong, North Carolina Agricultural and Technical State University
• Leslie B. Poole, Wake Forest University School of Medicine
• Jeremiah D. Keyes, Wake Forest University School of Medicine
• Robert H. Newman, North Carolina Agricultural and Technical State University

Document Type

Article

Publication Date

10-20-2023

Department

Department of Computer Science

Abstract

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are dysregulated in many pervasive diseases. Recently, we discovered that ERK1/2 is oxidized by signal-generated hydrogen peroxide in various cell types. Since the putative sites of oxidation lie within or near ERK1/2’s ligand-binding surfaces, we investigated how oxidation of ERK2 regulates interactions with the model substrates Sub-D and Sub-F. These studies revealed that ERK2 undergoes sulfenylation at C159 on its D-recruitment site surface and that this modification modulates ERK2 activity differentially between substrates. Integrated biochemical, computational, and mutational analyses suggest a plausible mechanism for peroxide-dependent changes in ERK2-substrate interactions. Interestingly, oxidation decreased ERK2’s affinity for some D-site ligands while increasing its affinity for others. Finally, oxidation by signal-generated peroxide enhanced ERK1/2’s ability to phosphorylate ribosomal S6 kinase A1 (RSK1) in HeLa cells. Together, these studies lay the foundation for examining crosstalk between redox- and phosphorylation-dependent signaling at the level of kinase-substrate selection.

Publisher's Statement

© 2023 The Authors. Publisher’s version of record: https://doi.org/10.1016/j.isci.2023.107817

Publication Title

iScience

Recommended Citation

Postiglione, A., Adams, L., Ekhator, E., Odelade, A., Patwardhan, S., Chaudhari, M., Pardue, A., Kumari, A., LeFever, W., Tornow, O., Kaoud, T., Neiswinger, J., Jeong, J., Parsonage, D., Nelson, K., KC, D., Furdui, C., Zhu, H., Wommack, A., Dalby, K., Dong, M., Poole, L., Keyes, J., & Newman, R. (2023). Hydrogen peroxide-dependent oxidation of ERK2 within its D-recruitment site alters its substrate selection. iScience, 26(10). http://doi.org/10.1016/j.isci.2023.107817
Retrieved from: https://digitalcommons.mtu.edu/michigantech-p2/100

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Version

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