Three loops of the common gamma chain ectodomain required for the binding of interleukin-2 and interleukin-7.
The common gamma chain (gammac), a subunit of the interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 receptors, contributes to both cytokine binding and subsequent signal transduction. Using a model-based site-directed mutagenesis strategy, we have identified residues of the mouse gammac extracellular domain that are required for normal gammac-dependent enhancement of IL-2 and IL-7 binding. One of these sites, Tyr-103, is homologous to key ligand-interacting residues in the growth hormone and erythropoietin receptors, whereas Cys-161, Cys-210, and Gly-211 may function indirectly by maintaining the functional conformation of gammac via formation of an intramolecular disulfide bond. These two cysteines are also required for the integrity of a putative epitope recognized by TUGm2, an antagonistic monoclonal antibody that blocks gammac-dependent cytokine binding and bioactivity. These results are consistent with the involvement of three predicted loops in gammac that contribute to the binding of both IL-2 and IL-7. Mutations in these loops have also been noted in the gammac gene of patients with X-linked severe combined immunodeficiency.
Olosz
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Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33101, USA.
Malek
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TR
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D001665:Binding Sites / Q000235:genetics; D019281:Dimerization; D008040:Genetic Linkage; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics; D012729:Sex Chromosome Aberrations / Q000235:genetics; D014960:X Chromosome
D007376:Interleukin-2; D015851:Interleukin-7; D018123:Receptors, Interleukin; D011994:Recombinant Proteins