The Role of Molecular Flexibility in Antigen Presentation and T Cell Receptor-Mediated Signaling.
The Role of Molecular Flexibility in Antigen Presentation and T Cell Receptor-Mediated Signaling.
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DOI：
10.3389/fimmu.2018.01657
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发表时间：
2018
影响因子：
7.3
通讯作者：
Margulies DH
中科院分区：
文献类型：
--
作者：
Natarajan K;Jiang J;May NA;Mage MG;Boyd LF;McShan AC;Sgourakis NG;Bax A;Margulies DH
抗原呈递是涉及多个步骤的细胞过程，从通过蛋白水解或异常合成产生肽开始，并将肽递送至细胞区室，在细胞区室中肽装载在MHC I类（MHC-I）或MHC II类（MHC-II）分子上。高亲和力免疫显性抗原的选择性装载和编辑由分子伴侣：与MHC-I相关的tapasin/TAP结合蛋白和与MHC-II相关的HLA-DM协调。一旦肽/MHC（pMHC）复合物组装完成，经过各种质量控制步骤，它们将被递送到细胞表面，在那里它们可用于通过CD 8+或CD 4 + T淋巴细胞上的αβ受体进行鉴定。此外，自然杀伤细胞受体对细胞表面肽/MHC-I复合物的识别在先天免疫应答的某些方面起调节作用。在过去的几十年里，抗原加工和呈递途径以及T细胞受体（TCR）介导的信号传导的许多组分已经通过生物化学、遗传学、免疫学和结构方法被广泛研究。然而，直到最近，动态方面的相互作用的肽与MHC，MHC分子伴侣，或pMHC与TCR的实验一直难以解决，虽然计算方法，如分子动力学（MD）模拟已经照亮。利用X射线晶体学、冷冻电子显微镜和多维核磁共振（NMR）光谱的研究开始揭示分子柔性的重要性，因为它涉及肽加载到MHC分子上、pMHC和TCR之间的相互作用以及随后的TCR介导的信号。此外，最近的结构和动态的见解如何分子伴侣定义肽的选择和微调的MHC展示的抗原库进行了讨论。在这里，我们提供了一个审查目前的知识，突出了实验数据获得的X射线晶体学和多维NMR方法。总的来说，这些研究结果强烈支持蛋白质可塑性和构象动力学在整个抗原加工和呈递途径中在决定抗原选择和识别中的多方面作用。
Antigen presentation is a cellular process that involves a number of steps, beginning with the production of peptides by proteolysis or aberrant synthesis and the delivery of peptides to cellular compartments where they are loaded on MHC class I (MHC-I) or MHC class II (MHC-II) molecules. The selective loading and editing of high-affinity immunodominant antigens is orchestrated by molecular chaperones: tapasin/TAP-binding protein, related for MHC-I and HLA-DM for MHC-II. Once peptide/MHC (pMHC) complexes are assembled, following various steps of quality control, they are delivered to the cell surface, where they are available for identification by αβ receptors on CD8+ or CD4+ T lymphocytes. In addition, recognition of cell surface peptide/MHC-I complexes by natural killer cell receptors plays a regulatory role in some aspects of the innate immune response. Many of the components of the pathways of antigen processing and presentation and of T cell receptor (TCR)-mediated signaling have been studied extensively by biochemical, genetic, immunological, and structural approaches over the past several decades. Until recently, however, dynamic aspects of the interactions of peptide with MHC, MHC with molecular chaperones, or of pMHC with TCR have been difficult to address experimentally, although computational approaches such as molecular dynamics (MD) simulations have been illuminating. Studies exploiting X-ray crystallography, cryo-electron microscopy, and multidimensional nuclear magnetic resonance (NMR) spectroscopy are beginning to reveal the importance of molecular flexibility as it pertains to peptide loading onto MHC molecules, the interactions between pMHC and TCR, and subsequent TCR-mediated signals. In addition, recent structural and dynamic insights into how molecular chaperones define peptide selection and fine-tune the MHC displayed antigen repertoire are discussed. Here, we offer a review of current knowledge that highlights experimental data obtained by X-ray crystallography and multidimensional NMR methodologies. Collectively, these findings strongly support a multifaceted role for protein plasticity and conformational dynamics throughout the antigen processing and presentation pathway in dictating antigen selection and recognition.
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影响因子：
32.4
作者：
Dong, Gang;Wearsch, Pamela A.;Peaper, David R.;Cresswell, Peter;Reinisch, Karin M.
通讯作者：
Reinisch, Karin M.
影响因子：
6.1
作者：
Anthis NJ;Clore GM
通讯作者：
Clore GM
影响因子：
3.7
作者：
Abualrous ET;Saini SK;Ramnarayan VR;Ilca FT;Zacharias M;Springer S
通讯作者：
Springer S
影响因子：
11.4
作者：
Chen, Mingnan;Bouvier, Marlene
通讯作者：
Bouvier, Marlene
DOI：
10.1073/pnas.1222342110
发表时间：
2013-02-26
影响因子：
11.1
作者：
Boyle, Louise H.;Hermann, Clemens;Trowsdale, John
通讯作者：
Trowsdale, John