Structural and functional consequences of altering a peptide MHC anchor residue
Structural and functional consequences of altering a peptide MHC anchor residue
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DOI：
10.4049/jimmunol.166.5.3345
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发表时间：
2001-03-01
影响因子：
4.4
通讯作者：
Fremont, DH
中科院分区：
文献类型：
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作者：
Kersh, GJ;Miley, MJ;Fremont, DH
为了更好地理解多种配体的TCR辨别，我们分析了两种Db肽/I-E-k复合物的晶体结构，这两种复合物的差异仅在于肽内P6锚位置处的单个氨基酸取代（E73 D），在1.9埃分辨率下对多个独立确定的结构进行的详细比较揭示，去除单个掩埋的亚甲基可以改变TCR的关键部分在肽P5-P8主链中观察到显著变化，以及在LeuP 8处的旋转异构体差异，类似于距离取代10埃的远端。在两种MHC II类分子的构象中没有观察到显著变化。配体的改变导致两个肽/MHC复合物产生大量的T细胞反应，这是不同的，基本上不重叠。对于Hb特异性T细胞3.L2，取代使配体的效力降低1000倍。可溶性3.L2 TCR以相似的亲和力结合两种肽/MHC复合物，尽管具有更快的动力学。这些结果突出了MHC Ag呈递中的细微变化对T细胞活化和信号传导的作用。
To better understand TCR discrimination of multiple ligands, we have analyzed the crystal structures of two Db peptide/I-E-k complexes that differ by only a single amino acid substitution at the P6 anchor position within the peptide (E73D), Detailed comparison of multiple independently determined structures at 1.9 Angstrom resolution reveals that removal of a single buried methylene group can alter a critical portion of the TCR recognition surface, Significant variance was observed in the peptide P5-P8 main chain as well as a rotamer difference at LeuP8, similar to 10 Angstrom distal from the substitution, No significant variations were observed in the conformation of the two MHC class II molecules. The ligand alteration results in two peptide/MHC complexes that generate bulk T cell responses that are distinct and essentially nonoverlapping. For the Hb-specific T cell 3.L2, substitution reduces the potency of the ligand 1000-fold. Soluble 3.L2 TCR binds the two peptide/MHC complexes with similar affinity, although with faster kinetics. These results highlight the role of subtle variations in MHC Ag presentation on T cell activation and signaling.