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
Artikel i vetenskaplig tidskrift, 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
Författare
Johanna J. Sjölander
Göteborgs universitet
Agata Tarczykowska
Göteborgs universitet
Cecilia Picazo Campos
Göteborgs universitet
Chalmers, Biologi och bioteknik, Systembiologi
Itziar Cossio
Göteborgs universitet
Itedale Namro Redwan
Göteborgs universitet
Chunxia Gao
Göteborgs universitet
Carlos Solano
Göteborgs universitet
Michel B. Toledano
Université Paris-Saclay
Morten Grötli
Göteborgs universitet
Mikael Molin
Chalmers, Biologi och bioteknik, Systembiologi
Göteborgs universitet
Per Sunnerhagen
Göteborgs universitet
Molecular and cellular biology
02707306 (ISSN) 10985549 (eISSN)
Vol. 40 7 e00346-19Ämneskategorier
Biokemi och molekylärbiologi
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Läkemedelskemi
DOI
10.1128/MCB.00346-19
PubMed
31932483