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

J 2024

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

HONZEJKOVA, Karolina; Dalibor KOSEK; Veronika OBSILOVA a Tomas OBSIL

Základní údaje

Originální název

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

Autoři

HONZEJKOVA, Karolina; Dalibor KOSEK; Veronika OBSILOVA a Tomas OBSIL

Vydání

elife, CAMBRIDGE, ELIFE SCIENCES PUBLICATIONS LTD, 2024, 2050-084X

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.400 v roce 2023

Kód RIV

RIV/00216224:90242/24:00139986

Organizační jednotka

CIISB III

DOI

https://doi.org/10.7554/eLife.95199

UT WoS

001193578900001

Klíčová slova anglicky

ASK1; protein kinase; thioredoxin; MAP3K; MAPK signaling; Human

Štítky

CF CRYO, ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 7. 5. 2025 12:52, Mgr. Eva Dubská

Anotace

V originále

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.

Návaznosti

90242, velká výzkumná infrastruktura

Název: CIISB III

Citovat

HONZEJKOVA, Karolina; Dalibor KOSEK; Veronika OBSILOVA a Tomas OBSIL. The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1. elife. CAMBRIDGE: ELIFE SCIENCES PUBLICATIONS LTD, 2024, roč. 13, March, s. 1-18. ISSN 2050-084X. Dostupné z: https://doi.org/10.7554/eLife.95199.

@article{2483738,
   author = {Honzejkova, Karolina and Kosek, Dalibor and Obsilova, Veronika and Obsil, Tomas},
   article_location = {CAMBRIDGE},
   article_number = {March},
   doi = {https://doi.org/10.7554/eLife.95199},
   keywords = {ASK1; protein kinase; thioredoxin; MAP3K; MAPK signaling; Human},
   language = {eng},
   issn = {2050-084X},
   journal = {elife},
   title = {The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1},
   url = {https://elifesciences.org/articles/95199},
   volume = {13},
   year = {2024}
}

TY  - JOUR
ID  - 2483738
AU  - Honzejkova, Karolina - Kosek, Dalibor - Obsilova, Veronika - Obsil, Tomas
PY  - 2024
TI  - The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1
JF  - elife
VL  - 13
IS  - March
SP  - 1-18
EP  - 1-18
PB  - ELIFE SCIENCES PUBLICATIONS LTD
SN  - 2050084X
KW  - ASK1
KW  - protein kinase
KW  - thioredoxin
KW  - MAP3K
KW  - MAPK signaling
KW  - Human
UR  - https://elifesciences.org/articles/95199
N2  - 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.
ER  -

HONZEJKOVA, Karolina; Dalibor KOSEK; Veronika OBSILOVA a Tomas OBSIL. The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1. \textit{elife}. CAMBRIDGE: ELIFE SCIENCES PUBLICATIONS LTD, 2024, roč.~13, March, s.~1-18. ISSN~2050-084X. Dostupné z: https://doi.org/10.7554/eLife.95199.

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