Computational and Functional Analysis of Structural Features in the ZAKα Kinase
The kinase ZAKα acts as the proximal sensor of translational impairment and ribotoxic stress, which results in the activation of the MAP kinases p38 and JNK. Despite recent insights into the functions and binding partners of individual protein domains in ZAKα, the mechanisms by which ZAKα binds ribo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/6/969 |
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| author | Valdemar Brimnes Ingemann Johansen Goda Snieckute Anna Constance Vind Melanie Blasius Simon Bekker-Jensen |
| author_facet | Valdemar Brimnes Ingemann Johansen Goda Snieckute Anna Constance Vind Melanie Blasius Simon Bekker-Jensen |
| author_sort | Valdemar Brimnes Ingemann Johansen |
| collection | DOAJ |
| description | The kinase ZAKα acts as the proximal sensor of translational impairment and ribotoxic stress, which results in the activation of the MAP kinases p38 and JNK. Despite recent insights into the functions and binding partners of individual protein domains in ZAKα, the mechanisms by which ZAKα binds ribosomes and becomes activated have remained elusive. Here, we highlight a short, thrice-repeated, and positively charged peptide motif as critical for the ribotoxic stress-sensing function of the Sensor (S) domain of ZAKα. We use this insight to demonstrate that the mutation of the SAM domain uncouples ZAKα activity from ribosome binding. Finally, we use 3D structural comparison to identify and functionally characterize an additional folded domain in ZAKα with structural homology to YEATS domains. These insights allow us to formulate a model for ribosome-templated ZAKα activation based on the re-organization of interactions between modular protein domains. In sum, our work both advances our understanding of the protein domains and 3D architecture of the ZAKα kinase and furthers our understanding of how the ribotoxic stress response is activated. |
| first_indexed | 2024-03-11T06:47:43Z |
| format | Article |
| id | doaj.art-82764bf3504443e39c62a174a4391ca2 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T06:47:43Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-82764bf3504443e39c62a174a4391ca22023-11-17T10:14:27ZengMDPI AGCells2073-44092023-03-0112696910.3390/cells12060969Computational and Functional Analysis of Structural Features in the ZAKα KinaseValdemar Brimnes Ingemann Johansen0Goda Snieckute1Anna Constance Vind2Melanie Blasius3Simon Bekker-Jensen4Center for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, DenmarkCenter for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, DenmarkCenter for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, DenmarkCenter for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, DenmarkCenter for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, DenmarkThe kinase ZAKα acts as the proximal sensor of translational impairment and ribotoxic stress, which results in the activation of the MAP kinases p38 and JNK. Despite recent insights into the functions and binding partners of individual protein domains in ZAKα, the mechanisms by which ZAKα binds ribosomes and becomes activated have remained elusive. Here, we highlight a short, thrice-repeated, and positively charged peptide motif as critical for the ribotoxic stress-sensing function of the Sensor (S) domain of ZAKα. We use this insight to demonstrate that the mutation of the SAM domain uncouples ZAKα activity from ribosome binding. Finally, we use 3D structural comparison to identify and functionally characterize an additional folded domain in ZAKα with structural homology to YEATS domains. These insights allow us to formulate a model for ribosome-templated ZAKα activation based on the re-organization of interactions between modular protein domains. In sum, our work both advances our understanding of the protein domains and 3D architecture of the ZAKα kinase and furthers our understanding of how the ribotoxic stress response is activated.https://www.mdpi.com/2073-4409/12/6/969ribotoxic stress responseZAKαJNKp38ribosomestranslation |
| spellingShingle | Valdemar Brimnes Ingemann Johansen Goda Snieckute Anna Constance Vind Melanie Blasius Simon Bekker-Jensen Computational and Functional Analysis of Structural Features in the ZAKα Kinase Cells ribotoxic stress response ZAKα JNK p38 ribosomes translation |
| title | Computational and Functional Analysis of Structural Features in the ZAKα Kinase |
| title_full | Computational and Functional Analysis of Structural Features in the ZAKα Kinase |
| title_fullStr | Computational and Functional Analysis of Structural Features in the ZAKα Kinase |
| title_full_unstemmed | Computational and Functional Analysis of Structural Features in the ZAKα Kinase |
| title_short | Computational and Functional Analysis of Structural Features in the ZAKα Kinase |
| title_sort | computational and functional analysis of structural features in the zakα kinase |
| topic | ribotoxic stress response ZAKα JNK p38 ribosomes translation |
| url | https://www.mdpi.com/2073-4409/12/6/969 |
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