Signal transduction of the erythropoietin receptor: role of the transmembrane region

In this review we present recent advances on the structure, conformation and signaling of the erythropoietin receptor (EpoR). Evidence from a number of studies support the concept that a specific dimeric receptor orientation is acquired on the plasma membrane after Epo binding and is required for promoting proliferation, survival and differentiation of erythroid progenitors. While X-ray crystal structures of the extracellular domain point to different dimeric orientations of unliganded and dimeric receptors, immunofluorescence co-patching studies and assays for transmembrane (TM) domain oligomerization suggest that, indeed, the EpoR is a preformed dimer in the absence of ligand. The EpoR TM domain self-assembles and, apparently, through one face it stabilizes by hydrogen bonds the EpoR dimeric inactive state and through another it contributes by leucine zipper type interactions to stabilizing the activated dimeric state. The extracellular juxtamembrane region is flexible and adopts a helix cap structure at the border with the TM domain, while an alpha-helical orientation of the cytosolic juxtamembrane region by the TM alpha-helix is important for activation of JAK2. We indicate on the receptor the regions that might be good novel targets for binding by future Epo-mimetics. A prime candidate would be the hinge region that separates the extracellular from the TM domain and such mimetics may be useful especially in cases where patients develop antibodies to erythropoietin after treatment.