Two Modes of β-Receptor Recognition Are Mediated by Distinct Epitopes on Mouse and Human Interleukin-3
Autor: | Bin Wen, James M. Murphy, Jin Dai, Jinglong Chen, Cameron L. Ewens, Shamaruh Mirza, Ian G. Young |
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Rok vydání: | 2010 |
Předmět: |
Gene isoform
MAP Kinase Signaling System Protein subunit DNA Mutational Analysis Molecular Sequence Data Interleukin-3 Receptor alpha Subunit Glutamic Acid Biochemistry Hematopoietic progenitor cell differentiation Epitope Cell Line Cytokine Receptor Common beta Subunit Epitopes Mice Animals Humans Protein Isoforms Amino Acid Sequence Binding site Receptor Molecular Biology Cell Proliferation Binding Sites Janus kinase 2 biology Cell Biology Janus Kinase 2 Molecular biology Enzyme Activation Mutation biology.protein Interleukin-3 Mutant Proteins Signal Transduction |
Zdroj: | Journal of Biological Chemistry. 285:22370-22381 |
ISSN: | 0021-9258 |
Popis: | The cytokine interleukin-3 (IL-3) is a critical regulator of inflammation and immune responses in mammals. IL-3 exerts its effects on target cells via receptors comprising an IL-3-specific alpha-subunit and common beta-subunit (beta c; shared with IL-5 and granulocyte-macrophage colony-stimulating factor) or a beta-subunit that specifically binds IL-3 (beta(IL-3); present in mice but not humans). We recently identified two splice variants of the alpha-subunit of the IL-3 receptor (IL-3R alpha) that are relevant to hematopoietic progenitor cell differentiation or proliferation: the full length ("SP1" isoform) and a novel isoform (denoted "SP2") lacking the N-terminal Ig-like domain. Although our studies demonstrated that each mouse IL-3 (mIL-3) R alpha isoform can direct mIL-3 binding to two distinct sites on the beta(IL-3) subunit, it has remained unclear which residues in mIL-3 itself are critical to the two modes of beta(IL-3) recognition and whether the human IL-3R alpha SP1 and SP2 orthologs similarly instruct human IL-3 binding to two distinct sites on the human beta c subunit. Herein, we describe the identification of residues clustering around the highly conserved A-helix residue, Glu(23), in the mIL-3 A- and C-helices as critical for receptor binding and growth stimulation via the beta(IL-3) and mIL-3R alpha SP2 subunits, whereas an overlapping cluster was required for binding and activation of beta(IL-3) in the presence of mIL-3R alpha SP1. Similarly, our studies of human IL-3 indicate that two different modes of beta c binding are utilized in the presence of the hIL-3R alpha SP1 or SP2 isoforms, suggesting a possible conserved mechanism by which the relative orientations of receptor subunits are modulated to achieve distinct signaling outcomes. |
Databáze: | OpenAIRE |
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