The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1

0585334 - FGÚ 2025 RIV GB eng J - Journal Article
Honzejková, K. - Košek, Dalibor - Obšilová, Veronika - Obšil, Tomáš
The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1.
eLife. Roč. 13, Mar 27 (2024), č. článku RP95199. ISSN 2050-084X. E-ISSN 2050-084X
R&D Projects: GA ČR(CZ) GA19-00121S
Research Infrastructure: CIISB III - 90242
Institutional support: RVO:67985823
Keywords : MAP3K * ASK1 kinase * Thioredoxin * cryo-EM
OECD category: Biochemistry and molecular biology
Impact factor: 7.7, year: 2022
Method of publishing: Open access
https://doi.org/10.7554/eLife.95199.2

Apoptosis signal-regulating kinase 1 (ASK1) is a crucial stress sensor, directing cells toward apoptosis, differentiation, and senescence via the p38 and JNK signaling pathways. ASK1 dysregulation has been associated with cancer and inflammatory, cardiovascular, and neurodegenerative diseases, among others. However, our limited knowledge of the underlying structural mechanism of ASK1 regulation hampers our ability to target this member of the MAP3K protein family towards developing therapeutic interventions for these disorders. Nevertheless, as a multidomain Ser/Thr protein kinase, ASK1 is regulated by a complex mechanism involving dimerization and interactions with several other proteins, including thioredoxin 1 (TRX1). Thus, the present study aims at structurally characterizing ASK1 and its complex with TRX1 using several biophysical techniques. As shown by cryo-EM analysis, in a state close to its active form, ASK1 is a compact and asymmetric dimer, which enables extensive interdomain and interchain interactions. These interactions stabilize the active conformation of the ASK1 kinase domain. In turn, TRX1 functions as a negative allosteric effector of ASK1, modifying the structure of the TRX1-binding domain and changing its interaction with the tetratricopeptide repeats domain. Consequently, TRX1 reduces access to the activation segment of the kinase domain. Overall, our findings not only clarify the role of ASK1 dimerization and inter-domain contacts but also provide key mechanistic insights into its regulation, thereby highlighting the potential of ASK1 protein-protein interactions as targets for anti-inflammatory therapy.
Permanent Link: https://hdl.handle.net/11104/0353047