T cell receptors are structures capable of initiating signaling in the absence of large conformational rearrangements.
T cell receptors are structures capable of initiating signaling in the absence of large conformational rearrangements.
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DOI：
10.1074/jbc.m111.332783
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发表时间：
2012-04-13
期刊：
影响因子：
--
通讯作者：
Davis SJ
中科院分区：
文献类型：
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作者：
Fernandes RA;Shore DA;Vuong MT;Yu C;Zhu X;Pereira-Lopes S;Brouwer H;Fennelly JA;Jessup CM;Evans EJ;Wilson IA;Davis SJ
背景：T细胞受体（TCR）通过一种未知的机制触发T细胞中的信号传导。结果如下：信号亚基CD3+的结构不会被信号诱导抗体改变，而阻断亚基间重排的突变不会影响信号传导。结论：抗体触发TCR信号传导而不诱导大的结构重排。意义：TCR触发通常可能发生在没有大的结构重排的情况下。已经提出T细胞受体（TCR）的天然和非天然配体（包括抗体）通过TCR复合物的细胞外区域内的亚基内或亚基间构象重排来诱导T细胞中的信号传导。我们已经研究了是否可以发现任何签名，这种假定的结构变化，在TCR触发抗体诱导，使用结晶和诱变为基础的方法。与促有丝分裂抗CD3 β抗体2C11复合的鼠CD3 β的晶体结构使得能够首次对来自单一物种的抗体配体和非配体形式的CD3 β进行直接结构比较，这揭示了抗体结合不会诱导CD3 β内的任何实质性重排。表面暴露的CD3+残基的饱和诱变，再加上抗体诱导的信号传导的突变复合物的测定，表明了一种新的配置的复合物内的CD3+是高度暴露的，并揭示了没有大的新的CD3+接口需要在抗体诱导的信号传导过程中形成。因此，TCR复合物似乎是能够在T细胞中启动细胞内信号传导而在组分亚基内或之间没有实质性结构重排的结构。我们的研究结果提出了一种可能性，即天然配体的信号也可能在受体没有大的结构重排的情况下启动。
Background: The T cell receptor (TCR) triggers signaling in T cells via an unknown mechanism. Results: The structure of the signaling subunit, CD3ϵ, is unchanged by signal-inducing antibodies, and mutations that would block intersubunit rearrangements do not affect signaling. Conclusion: Antibodies trigger TCR signaling without inducing large structural rearrangements. Significance: TCR triggering might generally occur in the absence of large structural rearrangements. Native and non-native ligands of the T cell receptor (TCR), including antibodies, have been proposed to induce signaling in T cells via intra- or intersubunit conformational rearrangements within the extracellular regions of TCR complexes. We have investigated whether any signatures can be found for such postulated structural changes during TCR triggering induced by antibodies, using crystallographic and mutagenesis-based approaches. The crystal structure of murine CD3ϵ complexed with the mitogenic anti-CD3ϵ antibody 2C11 enabled the first direct structural comparisons of antibody-liganded and unliganded forms of CD3ϵ from a single species, which revealed that antibody binding does not induce any substantial rearrangements within CD3ϵ. Saturation mutagenesis of surface-exposed CD3ϵ residues, coupled with assays of antibody-induced signaling by the mutated complexes, suggests a new configuration for the complex within which CD3ϵ is highly exposed and reveals that no large new CD3ϵ interfaces are required to form during antibody-induced signaling. The TCR complex therefore appears to be a structure that is capable of initiating intracellular signaling in T cells without substantial structural rearrangements within or between the component subunits. Our findings raise the possibility that signaling by native ligands might also be initiated in the absence of large structural rearrangements in the receptor.