Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin
Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin
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DOI：
10.1073/pnas.1807656116
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发表时间：
2019-03-12
影响因子：
11.1
通讯作者：
Achour, Adnane
中科院分区：
文献类型：
--
作者：
Hafstrand, Ida;Sayitoglu, Ece Canan;Achour, Adnane
向CD 8（+）T细胞的MHC-I表位呈递直接依赖于抗原加工期间的肽加载和选择。然而，MHC-I对肽的选择和结合的确切分子基础在很大程度上仍然是未知的。在肽加载复合物中，肽编辑器tapasin是选择MHC-I结合肽的关键。在这里，我们已经确定了MHC-I与肽交换相关的二肽GL复合的晶体结构的集合，以及单独或与候选表位组合的tapasin相关的勺环。这些结果结合突变分析，使我们能够提出一个分子模型的基础MHC-I肽选择塔帕辛。结合肽的N末端最可能首先结合在MHC-I肽结合裂缝的N末端和中间区域，在此之后测试肽C末端从MHC-I裂缝的F口袋中移出tapasin勺环的能力。我们的研究结果还表明，不同的MHC-I等位基因之间的肽选择的重要差异。
MHC-I epitope presentation to CD8(+) T cells is directly dependent on peptide loading and selection during antigen processing. However, the exact molecular bases underlying peptide selection and binding by MHC-I remain largely unknown. Within the peptide-loading complex, the peptide editor tapasin is key to the selection of MHC-I-bound peptides. Here, we have determined an ensemble of crystal structures of MHC-I in complex with the peptide exchange-associated dipeptide GL, as well as the tapasin-associated scoop loop, alone or in combination with candidate epitopes. These results combined with mutation analyses allow us to propose a molecular model underlying MHC-I peptide selection by tapasin. The N termini of bound peptides most probably bind first in the N-terminal and middle region of the MHC-I peptide binding cleft, upon which the peptide C termini are tested for their capacity to dislodge the tapasin scoop loop from the F pocket of the MHC-I cleft. Our results also indicate important differences in peptide selection between different MHC-I alleles.