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

Stefan N. Constantinescu, Lily Jun shen Huang, Hyung song Nam, Harvey F. Lodish

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

We report that the erythropoietin receptor cytosolic juxtamembrane region is conformationally rigid and contains a hydrophobic motif, composed of residues L253, I257, and W258, that is crucial for Janus kinase 2 (JAK2) activation and receptor signaling. Alanine insertion mutagenesis shows that the orientation of this motif and not its distance from the membrane bilayer is critical. Intragenic complementation studies suggest that L253 is contained within an α helix functionally continuous to the transmembrane α helix. The α-helical orientation of L253 is required not for JAK2 activation but for activated JAK2 to induce phosphorylation of the erythropoietin receptor. This motif is highly conserved among cytokine receptors and couples ligand-induced conformational changes in the receptor to intracellular activation of JAK2.

Original languageEnglish (US)
Pages (from-to)377-385
Number of pages9
JournalMolecular cell
Volume7
Issue number2
DOIs
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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