Identification and Structure of an MHC Class I-Encoded Protein with the Potential to Present N-Myristoylated 4-mer Peptides to T Cells
Identification and Structure of an MHC Class I-Encoded Protein with the Potential to Present N-Myristoylated 4-mer Peptides to T Cells
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DOI：
10.4049/jimmunol.1900087
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发表时间：
2019-06-15
影响因子：
4.4
通讯作者：
Sugita, Masahiko
中科院分区：
文献类型：
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作者：
Yamamoto, Yukie;Morita, Daisuke;Sugita, Masahiko
与宿主蛋白类似，病毒蛋白的n -肉豆蔻酰化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的“脂肽”Ags，被宿主ctl靶向。灵长类动物MHC i类编码蛋白Mamu-B*098先前被证明可以结合n -肉豆肉酰基化的5-聚肽。然而，存在识别更短的脂肽的T细胞，关于脂肽呈现的分子机制仍有待阐明。在这项研究中，我们证明MHC I类等位基因Mamu-B*05104结合来自病毒Nef蛋白的n -肉豆醇化4-mer肽（C14-Gly-Gly-Ala-Ile），将其呈递到ctl。系统发育树分析表明，这些经典的MHC I类等位基因并不密切相关；然而，高分辨率x射线晶体学分析表明，这两种分子都具有由超大的疏水性B口袋定义的脂质结合结构，以容纳酰基化甘氨酸（G1）作为锚点。C14-Gly-Gly-Ala-Ile的c端异亮氨酸（I4）锚定在F口袋上，这与Mamu-B*098不同，与肽呈递MHC I类分子HLA-B51几乎相同。两个中心氨基酸残基（G2和A3）仅暴露在外部供T细胞识别，A3上的甲基侧链构成了一个主要的T细胞表位，这表明与MHC i类长肽相比，脂肽的表位多样性受到高度限制。这些结构特征表明，呈递脂肽的MHC I类等位基因包括一个独特的MHC I类亚群，介导CTL激活的替代途径。
Similar to host proteins, N-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-B*098, was previously shown to bind N-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-B*05104, binds the N-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.