Document Detail

Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor.
MedLine Citation:
PMID:  11231127     Owner:  NLM     Status:  MEDLINE    
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.
K F Kubatzky; W Ruan; R Gurezka; J Cohen; R Ketteler; S S Watowich; D Neumann; D Langosch; U Klingmüller
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Current biology : CB     Volume:  11     ISSN:  0960-9822     ISO Abbreviation:  Curr. Biol.     Publication Date:  2001 Jan 
Date Detail:
Created Date:  2001-03-20     Completed Date:  2001-06-07     Revised Date:  2009-10-01    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  110-5     Citation Subset:  IM    
Max-Planck-Institute of Immunobiology, Freiburg 79108, Germany.
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MeSH Terms
Amino Acid Sequence
Blotting, Western
Cell Line
Cell Membrane / metabolism
Molecular Sequence Data
Precipitin Tests
Receptors, Erythropoietin / chemistry,  genetics,  metabolism*
Sequence Homology, Amino Acid
Signal Transduction*
Grant Support
CA77447/CA/NCI NIH HHS; R01 CA077447-02/CA/NCI NIH HHS; R01 CA077447-03/CA/NCI NIH HHS
Reg. No./Substance:
0/Receptors, Erythropoietin

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