The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif

We report that the erythropoietin receptor cytosolic juxtamembrane region i s conformationally rigid and contains a hydrophobic motif, composed of resi dues L-253, I-257, and W-258, that is crucial for Janus kinase 2 (JAK2) act ivation and receptor signaling. Alanine insertion mutagenesis shows that th e orientation of this motif and not its distance from the membrane bilayer is critical. Intragenic complementation studies suggest that L-253 is conta ined within an alpha helix functionally continuous to the transmembrane alp ha helix. The alpha -helical orientation of L-253 is required not for JAK2 activation but for activated JAK2 to induce phosphorylation of the erythrop oietin receptor. This motif is highly conserved among cytokine receptors an d couples ligand-induced conformational changes in the receptor to intracel lular activation of JAK2.