The Erythropoietin Receptor Transmembrane Domain Mediates Complex Formation with Viral Anemic and Polycythemic gp55 Proteins

Stefan N. Constantinescu, Tzvia Keren, William P. Russ, Iban Ubarretxena-Belandia, Yaniv Malka, Katharina F. Kubatzky, Donald M. Engelman, Harvey F. Lodish, Yoav I. Henis

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Erythropoietin receptor (EpoR) activation is crucial for mature red blood cell production. The murine EpoR can also be activated by the envelope protein of the polycythemic (P) spleen focus forming virus (SFFV), gp55-P. Due to differences in the TM sequence, gp55 of the anemic (A) strain SFFV, gp55-A, cannot efficiently activate the EpoR. Using antibody-mediated immunofluorescence co-patching, we show that the majority of EpoR forms hetero-oligomers at the cell surface with gp55-P and, surprisingly, with gp55-A. The EpoR TM domain is targeted by gp55-P and -A, as only chimeric receptors containing EpoR TM sequences oligomerized with gp55 proteins. Both gp55-P and gp55-A are homodimers on the cell surface, as shown by co-patching. However, when the homomeric interactions of the isolated TM domains were assayed by TOXCAT bacterial reporter system, only the TM sequence of gp55-P was dimerized. Thus, homo-oligomerization of gp55 proteins is insufficient for full EpoR activation, and a correct conformation of the dimer in the TM region is required. This is supported by the failure of gp55-A→P, a mutant protein whose TM domain can homo-oligomerize, to fully activate EpoR. As unliganded EpoR forms TM-dependent but inactive homodimers, we propose that the EpoR can be activated to different extents by homodimeric gp55 proteins, depending on the conformation of the gp55 protein dimer in the TM region.

Original languageEnglish (US)
Pages (from-to)43755-43763
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number44
DOIs
StatePublished - Oct 31 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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