S-7: A new cytokine receptor activation paradigm: Activation of JAK2 by the growth hormone receptor

The conformational changes required to transmit the GH binding signal from the extracellular domain of the GH receptor to its intracellular domain resulting in activation of JAK2 has been enigmatic. We have recently defined the first complete mechanistic model for JAK2 activation based on an archetypal cytokine receptor, the growth hormone receptor. To formulate this model we have used FRET to monitor positioning of the JAK2 binding motif, Jun-zipper receptor constructs to control receptor transmembrane (TM) helix position, atomistic modeling of TM helix interactions and docking of JAK2 kinase and inhibitory pseudokinase crystal structures with an opposing pair in trans [1]. Surprisingly, we found that activation of the receptor dimer induces a separation of its JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left handed crossover arrangement. This mechanism leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may generalize to other class I cytokine receptors.