Thioredoxin inhibits ASK1 by keeping it in reduced state

K. Honzejkova1,2, V. Obsilova2, T. Obsil1,2

1 Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic

 2 Department of Structural Biology of Signalling Proteins, Division BIOCEV, Institute of Physiology of the Czech Academy of Sciences, Vestec, Czech Republic

ASK1 (apoptosis signal-regulating kinase 1) is a member of MAPKKK protein family, which directs cell towards inflammation or apoptosis by means of either p38 or JNK signalling pathway [1, 2]. ASK1 dysregulation has been associated with cardiovascular [3], tumour [4] and neurodegenerative [5] diseases and ASK1 thus represents a prospective target for therapeutic intervention. ASK1 regulation involves both oligomerization and interaction with multiple binding partners. To better understand the principle of ASK1 activation, we investigated the oligomeric behaviour of the N-terminal part under different redox conditions. Our results revealed that the N-terminal part of ASK1 forms dimers in solution and that this dimerization is affected by redox conditions. Moreover, we also identified regions that form the dimerization interface of the N-terminal part of ASK1. In addition, our data suggest that the interaction between ASK1 and its inhibitor thioredoxin is considerably weaker in strong reducing conditions. Altogether, our findings provide new insights into the mechanism of ASK1 inhibition by TRX.

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This work was supported by the Czech Science Foundation (project 19-00121S) and the Grant Agency of Charles University (Grant No. 1160120).