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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F24%3A00585334" target="_blank" >RIV/67985823:_____/24:00585334 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/24:10479656 RIV/00216224:90242/24:00139986

Result on the web

<a href="https://doi.org/10.7554/eLife.95199.2" target="_blank" >https://doi.org/10.7554/eLife.95199.2</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.7554/eLife.95199.2" target="_blank" >10.7554/eLife.95199.2</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GA19-00121S" target="_blank" >GA19-00121S: Molecular basis of the 14-3-3 protein-dependent regulation of protein kinase activity</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

eLife

ISSN

2050-084X

e-ISSN

2050-084X

Volume of the periodical

13

Issue of the periodical within the volume

Mar 27

Country of publishing house

GB - UNITED KINGDOM

Number of pages

18

Pages from-to

RP95199

UT code for WoS article

001193578900001

EID of the result in the Scopus database

—