Structure function analysis of SH2D2A isoforms expressed in T cells reveals a crucial role for the proline rich region encoded by SH2D2A exon 7
Structure function analysis of SH2D2A isoforms expressed in T cells reveals a crucial role for the proline rich region encoded by SH2D2A exon 7
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DOI：
10.1186/1471-2172-7-15
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发表时间：
2006-07-13
期刊：
影响因子：
3
通讯作者：
Spurkland, Anne
中科院分区：
文献类型：
--
作者：
Granum, Stine;Sundvold-Gjerstad, Vibeke;Spurkland, Anne
背景：由SH 2D 2A编码的活化诱导的T细胞特异性衔接蛋白（TSAd）与Lck相互作用并调节其活性。存在TSAd mRNA的几种转录变体，但它们的生物学意义仍然未知。在这里，我们研究了SH 2D 2A转录本在活化的CD 4 + T细胞中的表达，并使用SH 2D 2A变体作为工具，以确定TSAd.Results功能重要的区域：TSAd被发现与Lck在人的CD 4 + T细胞体外相互作用。TSAd与Lck的相互作用有3种模式。TSAd aa 239 -256赋予与Lck-SH 3结构域的结合，而发现由SH 2D 2A外显子7编码的aa 239 -334内的四个酪氨酸中的一个或多个赋予与Lck-SH 2结构域的相互作用。最后发现TSAd-SH 2结构域与Lck相互作用。发现编码TSAd aa 239 - 334的SH 2D 2A外显子7包含不仅对于TSAd与Lck相互作用，而且对于TSAd调节Lck活性和TSAd易位到细胞核的信息是必需的。结论：TSAd和Lck可能通过几个不同的结构域相互作用，并且Lck与TSAd的相互作用在离体的CD 4 + T细胞中发生。编码aa 239 - 334的外显子7的选择性剪接导致TSAd的大部分蛋白质相互作用动机的丧失，并产生具有改变的调节Lck活性的能力的截短的TSAd分子。TSAd是否通过SH 2D 2A转录本的差异选择性剪接来调节仍有待确定。
Background: The activation induced T cell specific adapter protein (TSAd), encoded by SH2D2A, interacts with and modulates Lck activity. Several transcript variants of TSAd mRNA exist, but their biological significance remains unknown. Here we examined expression of SH2D2A transcripts in activated CD4+ T cells and used the SH2D2A variants as tools to identify functionally important regions of TSAd.Results: TSAd was found to interact with Lck in human CD4+ T cells ex vivo. Three interaction modes of TSAd with Lck were identified. TSAd aa239-256 conferred binding to the Lck-SH3 domain, whereas one or more of the four tyrosines within aa239-334 encoded by SH2D2A exon 7 was found to confer interaction with the Lck-SH2-domain. Finally the TSAd-SH2 domain was found to interact with Lck. The SH2D2A exon 7 encoding TSAd aa 239 - 334 was found to harbour information essential not only for TSAd interaction with Lck, but also for TSAd modulation of Lck activity and translocation of TSAd to the nucleus. All five SH2D2A transcripts were found to be expressed in CD3 stimulated CD4+ T cells.Conclusion: These data show that TSAd and Lck may interact through several different domains and that Lck TSAd interaction occurs in CD4+ T cells ex vivo. Alternative splicing of exon 7 encoding aa239 - 334 results in loss of the majority of protein interaction motives of TSAd and yields truncated TSAd molecules with altered ability to modulate Lck activity. Whether TSAd is regulated through differential alternative splicing of the SH2D2A transcript remains to be determined.