Structures of peptide-free and partially loaded MHC class I molecules reveal mechanisms of peptide selection
Structures of peptide-free and partially loaded MHC class I molecules reveal mechanisms of peptide selection
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DOI：
10.1038/s41467-020-14862-4
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发表时间：
2020-03-11
影响因子：
16.6
通讯作者：
Meijers, Rob
中科院分区：
文献类型：
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作者：
Anjanappa, Raghavendra;Garcia-Alai, Maria;Meijers, Rob
主要组织相容性复合体(MHC)I类分子选择性结合多肽，呈递给细胞毒性T细胞。这些分子的无肽状态还没有被很好地理解。在这里，我们描述了人类第I类分子的二硫键稳定的版本，它在没有多肽的情况下是稳定的，并且可以很容易地交换同源多肽。我们给出了HLA-A*02：01无肽状态的X射线晶体结构，以及A和F口袋中结合了二肽的结构。这些结构快照显示，排列在结合口袋内的氨基酸侧链以协调的方式在无肽解锁状态和结合多肽结合的锁定状态之间切换。分子动力学模拟表明，F口袋的打开和关闭影响相邻结合口袋中的多肽配体构象。我们认为，多肽结合是由MHC分子结合口袋之间的协同作用共同决定的。主要组织相容性复合体(MHC)I类分子在细胞表面呈现紧密结合的多肽，供细胞毒性T细胞识别。在这里，作者提出了二硫键稳定的人MHC I类分子在无肽状态下与二肽结合的晶体结构，发现结合多肽伴随着结合口袋中氨基酸侧链的协调构象开关。
Major Histocompatibility Complex (MHC) class I molecules selectively bind peptides for presentation to cytotoxic T cells. The peptide-free state of these molecules is not well understood. Here, we characterize a disulfide-stabilized version of the human class I molecule HLA-A*02:01 that is stable in the absence of peptide and can readily exchange cognate peptides. We present X-ray crystal structures of the peptide-free state of HLA-A*02:01, together with structures that have dipeptides bound in the A and F pockets. These structural snapshots reveal that the amino acid side chains lining the binding pockets switch in a coordinated fashion between a peptide-free unlocked state and a peptide-bound locked state. Molecular dynamics simulations suggest that the opening and closing of the F pocket affects peptide ligand conformations in adjacent binding pockets. We propose that peptide binding is co-determined by synergy between the binding pockets of the MHC molecule. Major Histocompatibility Complex (MHC) class I molecules present tightly binding peptides on the cell surface for recognition by cytotoxic T cells. Here, the authors present the crystal structures of a disulfide-stabilized human MHC class I molecule in the peptide-free state and bound with dipeptides, and find that peptide binding is accompanied by concerted conformational switches of the amino acid side chains in the binding pockets.