The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/95199 |
| _version_ | 1797238999605051392 |
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| author | Karolina Honzejkova Dalibor Kosek Veronika Obsilova Tomas Obsil |
| author_facet | Karolina Honzejkova Dalibor Kosek Veronika Obsilova Tomas Obsil |
| author_sort | Karolina Honzejkova |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-24T17:44:34Z |
| format | Article |
| id | doaj.art-fbfd17cff81c4de6912edeec406e7563 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-24T17:44:34Z |
| publishDate | 2024-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-fbfd17cff81c4de6912edeec406e75632024-03-27T14:26:25ZengeLife Sciences Publications LtdeLife2050-084X2024-03-011310.7554/eLife.95199The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1Karolina Honzejkova0Dalibor Kosek1Veronika Obsilova2https://orcid.org/0000-0003-4887-0323Tomas Obsil3https://orcid.org/0000-0003-4602-1272Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech RepublicInstitute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czech RepublicInstitute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czech RepublicDepartment of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic; Institute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czech RepublicApoptosis 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.https://elifesciences.org/articles/95199ASK1protein kinasethioredoxinMAP3KMAPK signaling |
| spellingShingle | Karolina Honzejkova Dalibor Kosek Veronika Obsilova Tomas Obsil The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1 eLife ASK1 protein kinase thioredoxin MAP3K MAPK signaling |
| title | The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1 |
| title_full | The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1 |
| title_fullStr | The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1 |
| title_full_unstemmed | The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1 |
| title_short | The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1 |
| title_sort | cryo em structure of ask1 reveals an asymmetric architecture allosterically modulated by trx1 |
| topic | ASK1 protein kinase thioredoxin MAP3K MAPK signaling |
| url | https://elifesciences.org/articles/95199 |
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