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-Structure paper
Title | Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation. |
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Journal, issue, pages | Science, Vol. 376, Issue 6589, Page 163-169, Year 2022 |
Publish date | Apr 8, 2022 |
Authors | Caleb R Glassman / Naotaka Tsutsumi / Robert A Saxton / Patrick J Lupardus / Kevin M Jude / K Christopher Garcia / |
PubMed Abstract | 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- ...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. |
External links | Science / PubMed:35271300 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.6 Å |
Structure data | EMDB-25715, PDB-7t6f: |
Chemicals | ChemComp-ADN: ChemComp-ADP: |
Source |
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Keywords | SIGNALING PROTEIN / signaling complex / Janus Kinase / JAK / oncogenic mutation / gain-of-function mutation / cytokine receptor |