Structural basis of Janus kinase trans-activation
Summary: Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs...
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Elsevier
2023-03-01
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Series: | Cell Reports |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723002127 |
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author | Nathanael A. Caveney Robert A. Saxton Deepa Waghray Caleb R. Glassman Naotaka Tsutsumi Stevan R. Hubbard K. Christopher Garcia |
author_facet | Nathanael A. Caveney Robert A. Saxton Deepa Waghray Caleb R. Glassman Naotaka Tsutsumi Stevan R. Hubbard K. Christopher Garcia |
author_sort | Nathanael A. Caveney |
collection | DOAJ |
description | Summary: Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs), resulting in the recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT)-family transcription factors. The structural arrangement of a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into the dimerization-dependent activation of JAKs and the role of oncogenic mutations in this process, the tyrosine kinase (TK) domains were separated by a distance not compatible with the trans-phosphorylation events between the TK domains. Here, we report the cryoelectron microscopy structure of a mouse JAK1 complex in a putative trans-activation state and expand these insights to other physiologically relevant JAK complexes, providing mechanistic insight into the crucial trans-activation step of JAK signaling and allosteric mechanisms of JAK inhibition. |
first_indexed | 2024-04-10T06:04:53Z |
format | Article |
id | doaj.art-8f1e23ec408e4692ae142b0442ba46ad |
institution | Directory Open Access Journal |
issn | 2211-1247 |
language | English |
last_indexed | 2024-04-10T06:04:53Z |
publishDate | 2023-03-01 |
publisher | Elsevier |
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series | Cell Reports |
spelling | doaj.art-8f1e23ec408e4692ae142b0442ba46ad2023-03-03T04:24:28ZengElsevierCell Reports2211-12472023-03-01423112201Structural basis of Janus kinase trans-activationNathanael A. Caveney0Robert A. Saxton1Deepa Waghray2Caleb R. Glassman3Naotaka Tsutsumi4Stevan R. Hubbard5K. Christopher Garcia6Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USADepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding authorSummary: Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs), resulting in the recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT)-family transcription factors. The structural arrangement of a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into the dimerization-dependent activation of JAKs and the role of oncogenic mutations in this process, the tyrosine kinase (TK) domains were separated by a distance not compatible with the trans-phosphorylation events between the TK domains. Here, we report the cryoelectron microscopy structure of a mouse JAK1 complex in a putative trans-activation state and expand these insights to other physiologically relevant JAK complexes, providing mechanistic insight into the crucial trans-activation step of JAK signaling and allosteric mechanisms of JAK inhibition.http://www.sciencedirect.com/science/article/pii/S2211124723002127janus kinasecryo-EMphosphorylationcytokine |
spellingShingle | Nathanael A. Caveney Robert A. Saxton Deepa Waghray Caleb R. Glassman Naotaka Tsutsumi Stevan R. Hubbard K. Christopher Garcia Structural basis of Janus kinase trans-activation Cell Reports janus kinase cryo-EM phosphorylation cytokine |
title | Structural basis of Janus kinase trans-activation |
title_full | Structural basis of Janus kinase trans-activation |
title_fullStr | Structural basis of Janus kinase trans-activation |
title_full_unstemmed | Structural basis of Janus kinase trans-activation |
title_short | Structural basis of Janus kinase trans-activation |
title_sort | structural basis of janus kinase trans activation |
topic | janus kinase cryo-EM phosphorylation cytokine |
url | http://www.sciencedirect.com/science/article/pii/S2211124723002127 |
work_keys_str_mv | AT nathanaelacaveney structuralbasisofjanuskinasetransactivation AT robertasaxton structuralbasisofjanuskinasetransactivation AT deepawaghray structuralbasisofjanuskinasetransactivation AT calebrglassman structuralbasisofjanuskinasetransactivation AT naotakatsutsumi structuralbasisofjanuskinasetransactivation AT stevanrhubbard structuralbasisofjanuskinasetransactivation AT kchristophergarcia structuralbasisofjanuskinasetransactivation |