Laboratory of Cell Regulation, Institute for Frontier Life and Medical Sciences, Kyoto University, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
J Immunol. 2019 Jun 15;202(12):3349-3358. doi: 10.4049/jimmunol.1900087. Epub 2019 May 1.
Similar to host proteins, -myristoylation occurs for viral proteins to dictate their pathological function. However, this lipid-modifying reaction creates a novel class of "lipopeptide" Ags targeted by host CTLs. The primate MHC class I-encoded protein, Mamu-B098, was previously shown to bind -myristoylated 5-mer peptides. Nevertheless, T cells exist that recognize even shorter lipopeptides, and much remains to be elucidated concerning the molecular mechanisms of lipopeptide presentation. We, in this study, demonstrate that the MHC class I allele, Mamu-B05104, binds the -myristoylated 4-mer peptide (C14-Gly-Gly-Ala-Ile) derived from the viral Nef protein for its presentation to CTLs. A phylogenetic tree analysis indicates that these classical MHC class I alleles are not closely associated; however, the high-resolution x-ray crystallographic analyses indicate that both molecules share lipid-binding structures defined by the exceptionally large, hydrophobic B pocket to accommodate the acylated glycine (G1) as an anchor. The C-terminal isoleucine (I4) of C14-Gly-Gly-Ala-Ile anchors at the F pocket, which is distinct from that of Mamu-B*098 and is virtually identical to that of the peptide-presenting MHC class I molecule, HLA-B51. The two central amino acid residues (G2 and A3) are only exposed externally for recognition by T cells, and the methyl side chain on A3 constitutes a major T cell epitope, underscoring that the epitopic diversity is highly limited for lipopeptides as compared with that for MHC class I-presented long peptides. These structural features suggest that lipopeptide-presenting MHC class I alleles comprise a distinct MHC class I subset that mediates an alternative pathway for CTL activation.
类似于宿主蛋白，病毒蛋白的 -豆蔻酰化作用决定了它们的病理功能。然而，这种脂质修饰反应产生了一类新型的“脂肽”Ag，被宿主 CTL 靶向。先前已经表明，灵长类 MHC Ⅰ类编码蛋白 Mamu-B098 结合了 -豆蔻酰化的 5 肽。然而，存在识别更短脂肽的 T 细胞，并且关于脂肽呈递的分子机制仍有许多需要阐明。在本研究中，我们证明 MHC Ⅰ类等位基因 Mamu-B05104 结合来自病毒 Nef 蛋白的 -豆蔻酰化 4 肽（C14-Gly-Gly-Ala-Ile），用于 CTL 的呈递。系统发育树分析表明，这些经典 MHC Ⅰ类等位基因没有密切相关；然而，高分辨率 X 射线晶体结构分析表明，这两种分子共享由异常大的疏水性 B 口袋定义的脂质结合结构，以容纳酰化甘氨酸（G1）作为锚定。C14-Gly-Gly-Ala-Ile 的 C 末端异亮氨酸（I4）锚定在 F 口袋，这与 Mamu-B*098 不同，与呈递 MHC Ⅰ类分子 HLA-B51 几乎相同。两个中心氨基酸残基（G2 和 A3）仅外部暴露以被 T 细胞识别，并且 A3 上的甲基侧链构成主要的 T 细胞表位，这表明与 MHC Ⅰ类呈递的长肽相比，脂肽的表位多样性受到高度限制。这些结构特征表明，脂肽呈递 MHC Ⅰ类等位基因构成了一个独特的 MHC Ⅰ类亚类，介导 CTL 激活的替代途径。
