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首页> 外文期刊>Molecular Immunology >Assessing the role of Asp 194 in the transmembrane domains of the alpha-chain of the high-affinity receptor complex for immunoglobulin E in signal transduction.
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Assessing the role of Asp 194 in the transmembrane domains of the alpha-chain of the high-affinity receptor complex for immunoglobulin E in signal transduction.

机译：评估Asp 194在免疫球蛋白E的高亲和力受体复合物的α链跨膜结构域中的作用，在信号转导中。

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摘要

The high-affinity receptor complex for IgE plays a pivotal role in allergic responses since cross-linking of the high-affinity IgE receptor (FcvarepsilonRI) on target cells initiates a signaling cascade facilitating release of inflammatory mediators causing allergic responses. The transmembrane regions of the ligand binding domains of the high-affinity IgE and low-affinity IgG receptors share an invariant motif (LFAVDTGL) containing a polar aspartate within a predominantly non-polar setting. The functional importance of this aspartate residue (D194) in FcvarepsilonRI-mediated receptor signaling was assessed by site-directed mutagenesis. Rat basophilic leukemia cells (RBL-2H3) transfected with the human IgE binding subunit (FcvarepsilonRIalpha) incorporating polar substitutions like asparagine (D194N) or threonine (D194T) resulted in the formation of a functional rat/human chimeric receptor complex. When activated via huIgE and antigen, cells transfected with these variant receptor subunits supported mediator release, intracellular calcium mobilisation and tyrosine phosphorylation of gamma-chain and Syk kinase while a non-polar substitution (D194L) gave rise to cell surface expression of the mutated receptor subunit but failed to initiate downstream signaling. No cell surface expression of huFcvarepsilonRIalpha gene constructs was observed when D194 was replaced with the non-polar Ile (D194I) residue of similar size, the larger positively charged Arg (D194R) or lysine (D194K) residues, or the negatively charged glutamate (D194E) and smaller polar Ser (D194S) non-polar Ala (D194A) and V (D194V). These observations highlight importance of the size and charge of amino acid residue at position 194 in determining IgE receptor subunit interactions, cell surface localization, and initiation of downstream signaling events.
机译：IgE的高亲和力受体复合物在过敏反应中起关键作用，因为高亲和力IgE受体（FcvarepsilonRI）在靶细胞上的交联启动信号级联反应，促进炎症介质的释放，引起过敏反应。高亲和力IgE和低亲和力IgG受体的配体结合结构域的跨膜区域共享一个恒定基序（LFAVDTGL），该基元在主要为非极性环境中包含极性天冬氨酸。通过定点诱变评估该天冬氨酸残基（D194）在FcvarepsilonRI介导的受体信号传导中的功能重要性。用结合了天冬酰胺（D194N）或苏氨酸（D194T）等极性取代的人IgE结合亚基（FcvarepsilonRIalpha）转染的大鼠嗜碱性粒细胞（RBL-2H3）导致了功能性大鼠/人嵌合受体复合物的形成。当通过huIgE和抗原激活时，转染了这些变异受体亚基的细胞支持介体释放，γ链和Syk激酶的细胞内钙动员和酪氨酸磷酸化，而非极性取代（D194L）则引起突变受体的细胞表面表达亚基，但未能启动下游信号传导。当用相似大小的非极性Ile（D194I）残基，较大的带正电的Arg（D194R）或赖氨酸（D194K）残基或带负电的谷氨酸盐（D194E）替换D194时，未观察到huFcvarepsilonRIalpha基因构建体的细胞表面表达。 ）和较小的极性Ser（D194S）非极性Ala（D194A）和V（D194V）。这些观察结果突出了在确定IgE受体亚基相互作用，细胞表面定位和下游信号转导事件的起始位置上194位氨基酸残基大小和电荷的重要性。

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