iScience (Oct 2023)
Hydrogen peroxide-dependent oxidation of ERK2 within its D-recruitment site alters its substrate selection
- Anthony E. Postiglione,
- Laquaundra L. Adams,
- Ese S. Ekhator,
- Anuoluwapo E. Odelade,
- Supriya Patwardhan,
- Meenal Chaudhari,
- Avery S. Pardue,
- Anjali Kumari,
- William A. LeFever,
- Olivia P. Tornow,
- Tamer S. Kaoud,
- Johnathan Neiswinger,
- Jun Seop Jeong,
- Derek Parsonage,
- Kimberly J. Nelson,
- Dukka B. Kc,
- Cristina M. Furdui,
- Heng Zhu,
- Andrew J. Wommack,
- Kevin N. Dalby,
- Ming Dong,
- Leslie B. Poole,
- Jeremiah D. Keyes,
- Robert H. Newman
Affiliations
- Anthony E. Postiglione
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA; Department of Biology, Wake Forest University, Winston-Salem, NC 27101, USA
- Laquaundra L. Adams
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA
- Ese S. Ekhator
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA
- Anuoluwapo E. Odelade
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA
- Supriya Patwardhan
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA
- Meenal Chaudhari
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA; Department of Computational Data Science and Engineering, North Carolina A&T State University, Greensboro, NC 27411, USA; Department of Mathematics and Computer Science, University of Virginia at Wise, Wise, VA 24293, USA
- Avery S. Pardue
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA
- Anjali Kumari
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA
- William A. LeFever
- Department of Chemistry, High Point University, High Point, NC 27268, USA; Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
- Olivia P. Tornow
- Department of Chemistry, High Point University, High Point, NC 27268, USA
- Tamer S. Kaoud
- Division of Chemical Biology and Medicinal Chemistry, The University of Texas at Austin, Austin, TX 78712, USA
- Johnathan Neiswinger
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biology, Belhaven University, Jackson, MS 39202, USA
- Jun Seop Jeong
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA
- Derek Parsonage
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Kimberly J. Nelson
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Dukka B. Kc
- Department of Computer Science, Michigan Technological University, Houghton, MI 49931, USA
- Cristina M. Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Heng Zhu
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Andrew J. Wommack
- Department of Chemistry, High Point University, High Point, NC 27268, USA
- Kevin N. Dalby
- Division of Chemical Biology and Medicinal Chemistry, The University of Texas at Austin, Austin, TX 78712, USA
- Ming Dong
- Department of Chemistry, North Carolina A&T State University, Greensboro, NC 27411, USA; Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28403, USA
- Leslie B. Poole
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Corresponding author
- Jeremiah D. Keyes
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; Department of Biology, Penn State University Behrend, Erie, PA 16563, USA; Magee-Womens Research Institute, Pittsburgh, PA 15213, USA; Corresponding author
- Robert H. Newman
- Department of Biology, North Carolina A&T State University, Greensboro, NC 27411, USA; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 10
p. 107817
Abstract
Summary: 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.
