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Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach

机译：B细胞活化的合成生物学：使用重建方法了解B细胞抗原受体的信号扩增

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摘要

Upon activation of the B cell antigen receptor (BCR), the spleen tyrosine kinase (Syk) and the Src family kinase Lyn phosphorylate tyrosines of the immunoreceptor tyrosine-based activation motif (ITAM) of Igα and Igβ which further serve as binding sites for the SH2 domains of these kinases. Using a synthetic biology approach, we dissect the roles of different ITAM residues of Igα in Syk activation. We found that a leucine to glycine mutation at the Y+3 position after the first ITAM tyrosine prevents Syk binding and activation. However, a pre-activated Syk can still phosphorylate this tyrosine in trans. Our data show that the formation of a Syk/ITAM initiation complex and trans-ITAM phosphorylation is crucial for BCR signal amplification. In contrast, the interaction of Lyn with the first ITAM tyrosine is not altered by the leucine to glycine mutation. In addition, our study suggests that an ITAM-bound Syk phosphorylates the non-ITAM tyrosine Y204 of Igα only in cis. Collectively, our reconstitution experiments suggest a model whereby first trans-phosphorylation amplifies the BCR signal and subsequently cis-phosphorylation couples the receptor to downstream signaling elements.
机译：在激活B细胞抗原受体（BCR）时，脾酪氨酸激酶（SYK）和SRC系列激酶Lyn磷酸化酪氨酸的Igα和Igβ的免疫聚酪氨酸酪氨酸的活化基序（Igβ），其进一步用作结合位点这些激酶的SH2结构域。利用合成生物方法，解剖了Igα不同ITAM残基在Syk激活中的作用。我们发现，在第一个ITAM酪氨酸后，在y + 3位在y + 3位置进行甘氨酸突变，防止Syk结合和活化。然而，预活化的Syk仍可在反式中磷酸化该酪氨酸。我们的数据表明，SYK / ITAM发酵复合物和Trans-ITAM磷酸化的形成对于BCR信号扩增至关重要。相反，Lyl与第一个ITAM酪氨酸的相互作用未被亮氨酸改变给甘氨酸突变。此外，我们的研究表明，ITAM-Counded Syk仅在CIS中磷酸化Igα的非ITAM酪氨酸Y204。统称，我们的重构实验表明了一种模型，由此第一反式磷酸化放大BCR信号，随后CIS-磷酸化将受体耦合到下游信号元件。

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  • 来源
    《Biological chemistry》 |2019年第4期|共9页
  • 作者

    YogeshKulathu; ChristaZuern; JianyingYang; MichaelReth;

  • 作者单位

    BIOSS Centre for Biological Signalling Studies Department of Molecular Immunology Institute of;

    BIOSS Centre for Biological Signalling Studies Department of Molecular Immunology Institute of;

    BIOSS Centre for Biological Signalling Studies Department of Molecular Immunology Institute of;

    BIOSS Centre for Biological Signalling Studies Department of Molecular Immunology Institute of;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    BCR; ITAM; Lyn; signal amplification; Syk; synthetic biology;

    机译：BCR;ITAM;LYN;信号放大;SYK;合成生物学;

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