Cytokine receptors are a family of transmembrane proteins including the erythropoietin receptor and the thrombopoietin receptor, among others. These proteins bind ligand (hormones) through an extracellular domain, transmitting a signal through the membrane that results in intracellular effects that include inhibition of apoptosis and usually mitogenesis. Though it is known that these effects are mediated by receptor dimerization and the Jak/STAT pathway, the precise mechanism by which these tasks are accomplished remains elusive.

Erythropoietin (Epo) stimulates erythropoiesis in hematopoietic stem cells. It does this by binding to the extracellular domain of the erythropoietin receptor, transmitting a signal through the transmembrane domain to the intracellular domain, resulting in the activation of the Jak/STAT pathway and production of red blood cells. It has been shown that the Epo receptor exists as preformed dimers, though the point of monomer association is a hotly contested issue. We believe that dimerization is mediated through the TM domain that locks the receptor in an “off” position in the absence of ligand. Epo binding results in a change in TM domain conformation that allows Jak2 to phosphorylate the cytoplasmic tyrosine residues on the receptor and other Jak2 molecules. This results in stimulation of mitogenesis and production of red blood cells.

While many groups have studied functional receptor mutants and a crystal structure of the extracellular domain exists, the complete structure remains to be solved. Using recombinantly expressed protein constructs and solution NMR spectroscopy, we are targeting the complete structure of the Epo receptor with the goal of understanding receptor activation. Insights into the structure-function of the Epo receptor may provide a general model for the activation of other cytokine receptors and could facilitate the development of pharmacotherapies for the treatment of erythropoietic diseases.