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首页> 外文期刊>Cytokine >Peptide insertions in domain 4 of hbeta(c), the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation.
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Peptide insertions in domain 4 of hbeta(c), the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation.

机译：肽插入hbeta（c）的域4中，它是GM-CSF，IL3和IL5的共享信号转导受体亚基，诱导配体非依赖性活化。

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摘要

A mutant form of the common beta-subunit of the GM-CSF, interleukin-3 (IL3) and IL5 receptors is activated by a 37 residue duplicated segment which includes the WSXWS motif and an adjacent, highly conserved, aliphatic/basic element. Haemopoietic expression of this mutant, hbeta(c)FIDelta, in mice leads to myeloproliferative disease. To examine the mechanism of activation of this mutant we targetted the two conserved motifs in each repeat for mutagenesis. Here we show that this mutant exhibits constitutive activity in BaF-B03 cells in the presence of mouse or human GM-CSF receptor alpha-subunit (GMRalpha) and this activity is disrupted by mutations of the conserved motifs in the first repeat. In the presence of these mutations the receptor reverts to an alternative conformation which retains responsiveness to human IL3 in a CTLL cell line co-expressing the human IL3 receptor alpha-subunit (hIL3Ralpha). Remarkably, the activated conformation is maintained in the presence of substitutions, deletions or replacement of the second repeat. This suggests that activation occurs due to insertion of extra sequence after the WSXWS motif and is not dependent on the length or specific sequence of the insertion. Thus hbeta(c) displays an ability to fold into functional receptor conformations given insertion of up to 37 residues in the membrane-proximal region. Constitutive activation most likely results from a specific conformational change which alters a dormant, inactive receptor complex, permitting functional association with GMRalpha and ligand-independent mitogenic signalling. Copyright 2001 Academic Press.
机译：GM-CSF，白介素-3（IL3）和IL5受体的常见β亚基的突变形式被37个残基重复的片段激活，该片段包括WSXWS基序和相邻的高度保守的脂族/碱性元件。该突变体hbeta（c）FIDelta在小鼠中的造血表达会导致骨髓增生性疾病。为了检查该突变体的激活机制，我们针对每个重复中的两个保守基元进行了诱变。在这里，我们显示该突变体在存在小鼠或人GM-CSF受体α亚基（GMRalpha）的情况下在BaF-B03细胞中显示出组成型活性，并且该活性被第一次重复中保守性基序的突变所破坏。在存在这些突变的情况下，受体还原为另一种构象，该构象在共表达人IL3受体α亚基（hIL3Ralpha）的CTLL细胞系中保留了对人IL3的响应性。显着地，活化的构象在第二重复序列的取代，缺失或替换的存在下得以维持。这表明激活是由于在WSXWS基序之后插入了额外的序列而发生的，而不取决于插入的长度或特定序列。因此，如果在膜近端区域插入多达37个残基，则hbeta（c）表现出折叠成功能性受体构象的能力。组成性激活很可能是由特定的构象变化引起的，该变化改变了休眠的，无活性的受体复合物，从而允许与GMRalpha和配体独立的促有丝分裂信号传导功能相关。版权所有2001，学术出版社。

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