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

Caleb R. Glassman, Naotaka Tsutsumi, Robert A. Saxton, Patrick J. Lupardus, Kevin M. Jude, K. Christopher Garcia

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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.

Original languageEnglish
Article numberabn8933
JournalScience
Volume376
Issue number6589
DOIs
Publication statusPublished - Apr 8 2022
Externally publishedYes

ASJC Scopus subject areas

  • General

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