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Publication Detail
Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Kubatzky KF, Ruan W, Gurezka R, Cohen J, Ketteler R, Watowich SS, Neumann D, Langosch D, Klingm├╝ller U
  • Publication date:
  • Pagination:
    110, 115
  • Journal:
    Curr Biol
  • Volume:
  • Issue:
  • Status:
  • Country:
  • Print ISSN:
  • PII:
  • Language:
  • Keywords:
    Amino Acid Sequence, Animals, Blotting, Western, Cell Line, Cell Membrane, Mice, Molecular Sequence Data, Mutation, Plasmids, Precipitin Tests, Receptors, Erythropoietin, Sequence Homology, Amino Acid, Signal Transduction
Hematopoietic cytokine receptors, such as the erythropoietin receptor (EpoR), are single membrane-spanning proteins. Signal transduction through EpoR is crucial for the formation of mature erythrocytes. Structural evidence shows that in the unliganded form EpoR exists as a preformed homodimer in an open scissor-like conformation precluding the activation of signaling. In contrast to the extracellular domain of the growth hormone receptor (GHR), the structure of the agonist-bound EpoR extracellular region shows only minimal contacts between the membrane-proximal regions. This evidence suggests that the domains facilitating receptor dimerization may differ between cytokine receptors. We show that the EpoR transmembrane domain (TM) has a strong potential to self interact in a bacterial reporter system. Abolishing self assembly of the EpoR TM by a double point mutation (Leu 240-Leu 241 mutated to Gly-Pro) impairs signal transduction by EpoR in hematopoietic cells and the formation of erythroid colonies upon reconstitution in erythroid progenitor cells from EpoR(-/-) mice. Interestingly, inhibiting TM self assembly in the constitutively active mutant EpoR R129C abrogates formation of disulfide-linked receptor homodimers and consequently results in the loss of ligand-independent signal transduction. Thus, efficient signal transduction through EpoR and possibly other preformed receptor oligomers may be determined by the dynamics of TM self assembly.
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