A Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to H2O2 and Is the Target of a Small Molecule
Journal article, 2020
Oxidation of a highly conserved cysteine (Cys) residue located in the kinase activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast Schizosaccharomyces pombe MAPKK Wis1, which belongs to the H2O2-responsive MAPK Sty1 pathway. Here, we show that H2O2 reversibly inactivates Wis1 through this residue (C458) in vitro We found that C458 is oxidized in vivo and that serine replacement of this residue significantly enhances Wis1 activation upon addition of H2O2 The allosteric MAPKK inhibitor INR119, which binds in a pocket next to the activation loop and C458, prevented the inhibition of Wis1 by H2O2in vitro and significantly increased Wis1 activation by low levels of H2O2in vivo We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the S. pombe MAPKK Wis1.
Sty1
Schizosaccharomyces pombe
cysteine oxidation
stress signaling
Author
Johanna J. Sjölander
University of Gothenburg
Agata Tarczykowska
University of Gothenburg
Cecilia Picazo Campos
University of Gothenburg
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Itziar Cossio
University of Gothenburg
Itedale Namro Redwan
University of Gothenburg
Chunxia Gao
University of Gothenburg
Carlos Solano
University of Gothenburg
Michel B. Toledano
University Paris-Saclay
Morten Grötli
University of Gothenburg
Mikael Molin
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
University of Gothenburg
Per Sunnerhagen
University of Gothenburg
Molecular and cellular biology
02707306 (ISSN) 10985549 (eISSN)
Vol. 40 7 e00346-19Subject Categories
Biochemistry and Molecular Biology
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Medicinal Chemistry
DOI
10.1128/MCB.00346-19
PubMed
31932483