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Structural models reveal how class 1 cytokine receptors activate Janus Kinase 2 (JAK2) signaling. Ligand binding induces receptor dimerization and TM helix rotation, activating JAK2 and influencing cell growth and oncogenesis.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Cellular Signaling
  • Structural Biology

Background:

  • Class 1 cytokine receptors (EPOR, TPOR, CSF3R, GHR, PRLR) are single-pass transmembrane glycoproteins regulating crucial cellular processes.
  • These receptors, upon ligand binding, form active signaling complexes with Janus Kinase 2 (JAK2).
  • Limited structural information exists for complete transmembrane (TM) receptor-cytokine-JAK2 complexes, hindering understanding of JAK-STAT pathway activation.

Approach:

  • Generated three-dimensional models of five human receptor complexes with cytokines and JAK2 using AlphaFold Multimer.
  • Employed a stepwise assembly strategy for large complexes (3220–4074 residues), validating models against experimental data.
  • Equilibrated models in explicit plasma membrane lipids for dynamic simulations.

Key Points:

  • Proposed a general activation mechanism involving ligand-induced receptor dimerization and TM α-helix rotation, leading to JAK2 activation.
  • Provided a potential binding mode for eltrombopag to the thrombopoietin receptor (TPOR) TM helices.
  • Offered insights into the molecular basis of oncogenic mutations, including potential non-canonical activation routes.

Conclusions:

  • The generated models provide a structural basis for understanding class 1 cytokine receptor activation and JAK-STAT signaling.
  • These models facilitate the study of oncogenic mutations and drug interactions.
  • Publicly available models support further research into receptor structure-function relationships and therapeutic target identification.