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Publication Detail
Packing density of the erythropoietin receptor transmembrane domain correlates with amplification of biological responses.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Becker V, Sengupta D, Ketteler R, Ullmann GM, Smith JC, Klingm├╝ller U
  • Publication date:
    11/11/2008
  • Pagination:
    11771, 11782
  • Journal:
    Biochemistry
  • Volume:
    47
  • Issue:
    45
  • Country:
    United States
  • Language:
    eng
  • Keywords:
    Animals, Asparagine, Binding Sites, Cell Line, Cell Membrane, Cell Proliferation, Dimerization, Flow Cytometry, Immunoblotting, Immunoprecipitation, Mice, Microscopy, Fluorescence, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mutation, NIH 3T3 Cells, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt, Receptors, Erythropoietin, Signal Transduction
Abstract
The formation of signal-promoting dimeric or oligomeric receptor complexes at the cell surface is modulated by self-interaction of their transmembrane (TM) domains. To address the importance of TM domain packing density for receptor functionality, we examined a set of asparagine mutants in the TM domain of the erythropoietin receptor (EpoR). We identified EpoR-T242N as a receptor variant that is present at the cell surface similar to wild-type EpoR but lacks visible localization in vesicle-like structures and is impaired in efficient activation of specific signaling cascades. Analysis by a molecular modeling approach indicated an increased interhelical distance for the EpoR-T242N TM dimer. By employing the model, we designed additional mutants with increased or decreased packing volume and confirmed a correlation between packing volume and biological responsiveness. These results propose that the packing density of the TM domain provides a novel layer for fine-tuned regulation of signal transduction and cellular decisions.
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