Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation
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- Caleb R. Glassman
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Naotaka Tsutsumi
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Robert A. Saxton
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Patrick J. Lupardus
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- Kevin M. Jude
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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- K. Christopher Garcia
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Description
<jats:p>Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom–resolution cryo–electron microscopy structure of full-length JAK1 complexed with a cytokine receptor intracellular domain Box1 and Box2 regions captured as an activated homodimer bearing the valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit, the dimerization of which is mediated by close-packing of the pseudokinase (PK) domains from the monomeric subunits. The oncogenic VF mutation lies within the core of the JAK1 PK interdimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The carboxy-terminal tyrosine kinase domains are poised for transactivation and to phosphorylate the receptor STAT (signal transducer and activator of transcription)–recruiting motifs projecting from the overhanging FERM (four-point-one, ezrin, radixin, moesin)–SH2 (Src homology 2)-domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals opportunities for selective therapeutic targeting of oncogenic JAK signaling.</jats:p>
Journal
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- Science
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Science 376 (6589), 163-169, 2022-04-08
American Association for the Advancement of Science (AAAS)
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Details 詳細情報について
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- CRID
- 1360580232430935808
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- ISSN
- 10959203
- 00368075
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- Data Source
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- Crossref
- KAKEN
