Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
    • Publication Information:
      Publication: : Washington, DC : American Association for the Advancement of Science
      Original Publication: New York, N.Y. : [s.n.] 1880-
    • Subject Terms:
      Janus Kinase 1*/chemistry ; Janus Kinase 1*/metabolism ; Receptors, Cytokine*/chemistry ; src Homology Domains*; Allosteric Regulation ; Cryoelectron Microscopy ; Enzyme Activation ; Humans ; Mutation ; Myeloproliferative Disorders/enzymology ; Myeloproliferative Disorders/genetics ; Phosphorylation ; Protein Multimerization ; STAT Transcription Factors/metabolism
    • 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-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.
    • Comments:
      Comment in: Science. 2022 Apr 8;376(6589):139-140. (PMID: 35389811)
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    • Grant Information:
      R37 AI051321 United States AI NIAID NIH HHS; United States HHMI Howard Hughes Medical Institute
    • Accession Number:
      0 (Receptors, Cytokine)
      0 (STAT Transcription Factors)
      EC 2.7.10.2 (Janus Kinase 1)
    • Publication Date:
      Date Created: 20220310 Date Completed: 20220415 Latest Revision: 20230409
    • Publication Date:
      20240829
    • Accession Number:
      PMC9306331
    • Accession Number:
      10.1126/science.abn8933
    • Accession Number:
      35271300