Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition
Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition
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DOI：
10.1074/jbc.m113.490664
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发表时间：
2013-08-23
影响因子：
4.8
通讯作者：
Baker, Brian M.
中科院分区：
文献类型：
--
作者：
Hawse, William F.;Gloor, Brian E.;Baker, Brian M.
T细胞利用α-βT细胞受体(TCR)识别抗原提呈细胞表面I类主要组织相容性复合体蛋白(PMHC)提呈的抗原肽。TCR和多肽的灵活性在抗原识别和识别中起着重要作用。不太清楚的是MHC蛋白中灵活性的作用；尽管最近的观察表明MHC中的流动性可以以一种依赖于肽的方式影响TCR识别，但这种行为的程度尚不清楚。在这里，利用氢/氢交换、荧光各向异性和结构分析，我们表明I类MHC蛋白HLA-A*0201的多肽结合槽的柔性随着多肽的不同而显著不同。这些变异延伸到整个结合沟，影响与TCR以及免疫系统其他激活和抑制受体接触的区域。我们的结果与蛋白质结构和动力学的统计力学模型是一致的，在该模型中，不同多肽的结合改变了MHC构象系综中亚态的布居和交换动力学。改变的MHC灵活性将影响受体的参与，影响构象适应，与受体识别相关的熵惩罚，以及结合能力状态的群体。我们的结果强调了免疫识别的“改变的自我”机制以前未被认识到的一个方面，并对细胞免疫中的特异性、交叉反应性和抗原性有影响。
T cells use the alpha beta Tcell receptor (TCR) to recognize antigenic peptides presented by class I major histocompatibility complex proteins (pMHCs) on the surfaces of antigen-presenting cells. Flexibility in both TCRs and peptides plays an important role in antigen recognition and discrimination. Less clear is the role of flexibility in the MHC protein; although recent observations have indicated that mobility in the MHC can impact TCR recognition in a peptide-dependent fashion, the extent of this behavior is unknown. Here, using hydrogen/deuterium exchange, fluorescence anisotropy, and structural analyses, we show that the flexibility of the peptide binding groove of the class I MHC protein HLA-A*0201 varies significantly with different peptides. The variations extend throughout the binding groove, impacting regions contacted by TCRs as well as other activating and inhibitory receptors of the immune system. Our results are consistent with statistical mechanical models of protein structure and dynamics, in which the binding of different peptides alters the populations and exchange kinetics of sub-states in the MHC conformational ensemble. Altered MHC flexibility will influence receptor engagement, impacting conformational adaptations, entropic penalties associated with receptor recognition, and the populations of binding-competent states. Our results highlight a previously unrecognized aspect of the "altered self" mechanism of immune recognition and have implications for specificity, cross-reactivity, and antigenicity in cellular immunity.