The effect of mutations on the alloreactive T cell receptor/peptide-MHC interface structure: a molecular dynamics study.
The effect of mutations on the alloreactive T cell receptor/peptide-MHC interface structure: a molecular dynamics study.
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突变对同种异体反应性 T 细胞受体/肽-MHC 界面结构的影响：分子动力学研究。
DOI：
10.1021/jp202471d
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Chakraborty,ArupK
中科院分区：
文献类型：
--
作者：
Wolfson,MikhailY;Nam,Kwangho;Chakraborty,ArupK
T细胞协调适应性的、病原体特异性的免疫反应。T细胞有一个表面受体(称为TCR)，其配体是由多肽(来源于病原体或宿主蛋白)和主要组织相容性复合体蛋白(MHC)组成的复合体(PMHC)。不同宿主的MHC蛋白不同。在器官移植过程中，宿主TCR与存在于具有不同遗传差异的MHC的复合体中的多肽相互作用。这通常会引起一种强烈的免疫反应：同种异体反应。对同种异体反应蛋白相互作用的研究已经产生了一个令人困惑的结果。一些结晶学研究得出结论，改变TCR多肽结合区基本上不影响同种异体反应TCR/MHC界面，表明多肽不影响界面。另一项生化研究从突变数据得出结论，不同的多肽可以改变与相同TCR的结合界面。为了探索这个谜题的起源，我们用分子动力学模拟研究了TCR/pMHC界面对多肽和TCR变化的依赖性。我们的模拟表明，TCR在pMHC上的足迹对TCR肽结合环的突变不敏感，但肽突变可以使TCR/pMHC接触发生多个局部变化。因此，我们的结果表明，结构和突变数据并不冲突，并揭示了同种异体反应TCR/pMHC界面的特征受TCR和多肽的影响是多么细微而重要。
T cells orchestrate adaptive, pathogen-specific immune responses. T cells have a surface receptor (called TCR) whose ligands are complexes (pMHCs) of peptides (derived from pathogens or host proteins) and major histocompatibility complex proteins (MHCs). MHC proteins vary between hosts. During organ transplants, host TCRs interact with peptides present in complex with genetically different MHCs. This usually causes a vigorous immune response: alloreactivity. Studies of alloreactive protein interactions have yielded results that present a puzzle. Some crystallographic studies concluded that the alloreactive TCR/MHC interface is essentially unaffected by changing the TCR peptide-binding region, suggesting that the peptide does not influence the interface. Another biochemical study concluded from mutation data that different peptides can alter the binding interface with the same TCR. To explore the origin of this puzzle, we used molecular dynamics simulations to study the dependence of the TCR/pMHC interface on changes in both the peptide and the TCR. Our simulations show that the footprint of the TCR on the pMHC is insensitive to mutations of the TCR peptide-binding loops, but peptide mutations can make multiple local changes to TCR/pMHC contacts. Therefore, our results demonstrate that the structural and mutation data do not conflict and reveal how subtle, but important, characteristics of the alloreactive TCR/pMHC interface are influenced by the TCR and the peptide.