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|Title:||Interacting residues ion the extracellular region of the common β subunit of the human granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 receptors involved in constitutive activation|
|Other Titles:||Interacting residues ion the extracellular region of the common beta subunit of the human granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 receptors involved in constitutive activation|
|Citation:||Journal of Biological Chemistry, 1996; 271(47):29707-29714|
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Brendan J. Jenkins, Christopher J. Bagley, Joanna Woodcock, Angel F. Lopez and Thomas J. Gonda|
|Abstract:||A previous study using random mutagenesis identified an activating mutation in the common β subunit (hβc) of the human granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5 receptors in which an isoleucine residue (Ile374) in the extracellular region of hβc is replaced by asparagine (Jenkins, B. J., D'Andrea, R., and Gonda, T. J. (1995) EMBO J 14, 4276-4287). To investigate the mechanism by which this mutation (I374N) acts, we employed site-directed mutagenesis to explore predictions based on a structural model of hβc. We focused on possible interactions between Ile374 and other hydrophobic residues in its vicinity and found that replacement of two such residues, Leu356 and Trp358, with asparagine resulted in constitutive activation of hβc. Hydrophilic substitutions at both of these positions and at position 374 resulted in the greatest degree of activation, as measured by the growth rate of factor-independent cells, while hydrophobic substitutions had lesser or no effects. Moreover, these “weak” substitutions appeared to synergize, since factor-independent cells expressing the double mutants I374F/W358F and I374F/L356A showed substantially higher growth rates than the single mutants. Taken together, these results suggest that Ile374 normally interacts with Leu356 and Trp358, and that disruption of these interactions results in a conformational change in hβc that leads to constitutive activity. A model relating this notion to the predicted structure and to ligand- and α subunit-dependent activation of hβc is proposed.|
|Keywords:||Cell Line; Humans; Amino Acids; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-3; Receptors, Interleukin; Mutagenesis, Site-Directed; Amino Acid Sequence; Sequence Homology, Amino Acid; Models, Molecular; Molecular Sequence Data; Receptors, Interleukin-5|
|Rights:||© 1996 by The American Society for Biochemistry and Molecular Biology, Inc.|
|Appears in Collections:||Medicine publications|
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