Growth hormone receptor

The growth hormone receptor is a membrane receptor that recognizes growth hormone and couples its binding to intracellular signaling through the associated tyrosine kinase JAK2. The receptor binds the extracellular hormone, while JAK2 supplies a catalytic signaling activity on the cytoplasmic side. Binding and kinase activation are related but distinct events.^[ref]

A 1992 crystal structure resolved one growth hormone molecule bound to two receptor extracellular domains at 2.8-angstrom resolution. The hormone contacted the two receptor molecules through different surfaces. This establishes an informative stoichiometry and geometry, but the isolated extracellular complex does not by itself show all movements or phosphorylation reactions in a living membrane.^[ref]

Later experiments tested the geometry inside receptor dimers. A 2014 study used Förster resonance energy transfer to monitor the relative positions of receptor motifs that bind JAK2, together with engineered receptors and molecular modeling. The resulting model linked receptor rearrangement to changes in how kinase and inhibitory pseudokinase regions interact.^[ref]

An important consequence is that measuring hormone occupancy alone cannot specify the signaling output. Two receptor configurations can have bound ligand yet position their intracellular partners differently. Experiments that separately measure binding, geometry and downstream kinase activity are therefore more informative than assuming that every occupied receptor is equally active.