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.

stress signaling

Schizosaccharomyces pombe

cysteine oxidation

Sty1

Författare

Johanna J. Sjölander

Göteborgs universitet

Agata Tarczykowska

Göteborgs universitet

Cecilia Picazo

Göteborgs universitet

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

10985549 (eISSN)

Vol. 40 7

Ämneskategorier

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

Mer information

Senast uppdaterat

2020-04-29