Crystal structure of the ternary complex of TCR, MHC class I and lipopeptides
Crystal structure of the ternary complex of TCR, MHC class I and lipopeptides
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DOI：
10.1093/intimm/dxaa050
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发表时间：
2020-12-01
影响因子：
4.4
通讯作者：
Sugita, Masahiko
中科院分区：
文献类型：
--
作者：
Morita, Daisuke;Iwashita, Chieri;Sugita, Masahiko
在一些病毒蛋白中，14碳脂肪酸(肉豆蔻酸)与N-末端甘氨酸残基发生共价偶联，称为N-肉豆蔻酸化，以决定其病理功能。然而，这种蛋白质脂化反应是由宿主细胞毒性T淋巴细胞监控的，这些T淋巴细胞能够识别主要组织相容性复合体(MHC)I类分子背景下的N末端脂肽片段。例如，在人类艾滋病的恒河猴模型中，经典的MHC I类异构体MAMU-B*05104被证明与SIVNef衍生的4-聚脂肽(肉豆蔻酸-甘氨酸-甘氨酸-丙氨酸-Ile；C14nef4)结合，并将它们呈递给CD8(+)T细胞系SN45。这些存在于MHC-I类分子中的脂肽比传统的MHC-I类呈现的8-10肽暴露出更短的肽链，并且α-βT细胞受体(TCR)识别脂肽的分子机制目前尚不清楚。对SN45TCRα和β与C14nef4结合的MAMU-B*05104络合物共结晶形式的X射线晶体分析表明，N-肉豆蔻酰化甘氨酸残基的酰胺基团通过在其氮原子和CDR3β第101位的Glu侧链之间建立唯一的氢键来提供主要的T细胞表位。相应地，该位置的Glu到Ala突变导致脂肽识别的丧失。另一方面，TCR位于远离C14nef4的多肽部分，没有观察到强烈的相互作用。因此，这些观察结果为TCRs识别脂肽提供了新的结构见解，这与肽识别的一般分子原理形成了鲜明对比。
The covalent conjugation of a 14-carbon fatty acid (myristic acid) to the N-terminal Gly residue, termed N-myristoylation, occurs in some viral proteins to dictate their pathological function. This protein lipidation reaction, however, is monitored by host cytotoxic T lymphocytes that are capable of recognizing N-terminal lipopeptide fragments in the context of major histocompatibility complex (MHC) class I molecules. In a rhesus model of human AIDS, for example, the classical MHC class I allomorph, Mamu-B*05104, was shown to bind SIV Nef-derived 4-mer lipopeptides (myristic acid-Gly-Gly-Ala-Ile; C14nef4) and present them to the CD8(+) T-cell line, SN45. These lipopeptides accommodated in MHC class I molecules expose much shorter peptide chains than conventional MHC class I-presented 8-10-mer peptides, and the molecular mechanisms by which alpha beta T-cell receptors (TCRs) recognize lipopeptides currently remain unclear. An X-ray crystallographic analysis of the SN45 TCR alpha and beta heterodimer in a form that was co-crystallized with the C14nef4-bound Mamu-B*05104 complex indicated that the amide group of the N-myristoylated glycine residue offered a primary T-cell epitope by establishing a sole hydrogen bond between its nitrogen atom and the side chain of Glu at position 101 of CDR3 beta. Accordingly, the Glu to Ala mutation at this position resulted in the loss of lipopeptide recognition. On the other hand, TCRs were positioned remotely from the peptide portion of C14nef4, and strong interactions were not observed. Thus, these observations provide novel structural insights into lipopeptide recognition by TCRs, which contrast sharply with the general molecular principle of peptide recognition.Y