Session: S04-GH at the Cutting Edge
Room 303 (Moscone Center)
The conformational changes required to transmit the GH binding signal from the extracellular domain of the GH receptor to its intracellular domain which result in activation of JAK2, are poorly understood. We have used techniques including FRET, receptor mutagenesis and cysteine crosslinking together with modeling of receptor transmembrane helix interactions in lipid membranes and docking of the JAK2 kinase and pseudokinase crystal structures to formulate a new model for receptor activation. In this first complete mechanistic model of GHR activation we define the molecular realignment of the transmembrane domains resulting from GH binding. We show that binding causes the JAK2 binding Box1 motifs of the intracellular domain of the receptor to move apart, however this movement is still able to bring the kinase domains of JAK2 in close proximity while moving the inhibitory pseudokinase domains further apart. This facilitates pairing of the catalytic domains and results in Jak2 activation.