Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid in its transmembrane domain

Stefan N. Constantinescu, Xuedong Liu, Wendy Beyer, Amy Fallon, Srinivasan Shekar, Yoav I. Henis, Steven O. Smith, Harvey F. Lodish

Research output: Contribution to journalArticlepeer-review

Abstract

The spleen focus forming virus (SFFV) gp55-P envelope glycoprotein specifically binds to and activates murine erythropoietin receptors (EpoRs) coexpressed in the same cell, triggering proliferation of erythroid progenitors and inducing erythroleukemia. Here we demonstrate specific interactions between the single transmembrane domains of the two proteins that are essential for receptor activation. The human EpoR is not activated by gp55-P but by mutation of a single amino acid, L238, in its transmembrane sequence to its murine counterpart serine, resulting in its ability to be activated. The converse mutation in the murine EpoR (S238L) abolishes activation by gp55-P. Computational searches of interactions between the membrane-spanning segments of murine EpoR and gp55-P provide a possible explanation: the face of the EpoR transmembrane domain containing S238 is predicted to interact specifically with gp55-P but not gp55-A, a variant which is much less effective in activating the murine EpoR. Mutational studies on gp55-P M390, which is predicted to interact with S238, provide additional support for this model. Mutation of M390 to isoleucine, the corresponding residue in gp55-A, abolishes activation, but the gp55-P M390L mutation is fully functional. gp55-P is thought to activate signaling by the EpoR by inducing receptor oligomerization through interactions involving specific transmembrane residues.

Original languageEnglish
Pages (from-to)3334-3347
Number of pages14
JournalEMBO Journal
Volume18
Issue number12
DOIs
StatePublished - 15 Jun 1999

Keywords

  • Epo receptor signaling
  • Red cell formation
  • SFFV-gp55 env proteins
  • Transmembrane coiled-coil interactions

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