Open AccessA Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to H2O2 and Is the Target of a Small Molecule
Author(s) -
Johanna Johansson Sjölander,
Agata Tarczykowska,
Cecilia Picazo,
Itziar Cossío,
Itedale Namro Redwan,
Chunxia Gao,
Carlos Solano,
Michel B. Toledano,
Morten Grøtli,
Mikael Molin,
Per Sunnerhagen
Publication year - 2020
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00346-19
Subject(s) - schizosaccharomyces pombe , biology , cysteine , protein kinase a , kinase , allosteric regulation , serine , mapk/erk pathway , biochemistry , residue (chemistry) , mitogen activated protein kinase kinase , c raf , schizosaccharomyces , yeast , microbiology and biotechnology , signal transduction , mitogen activated protein kinase , enzyme , saccharomyces cerevisiae
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 H 2 O 2 -responsive MAPK Sty1 pathway. Here, we show that H 2 O 2 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 H 2 O 2 The allosteric MAPKK inhibitor INR119, which binds in a pocket next to the activation loop and C458, prevented the inhibition of Wis1 by H 2 O 2 in vitro and significantly increased Wis1 activation by low levels of H 2 O 2 in 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.