Crystal structures of lysophospholipid-bound MHC class I molecules
Crystal structures of lysophospholipid-bound MHC class I molecules
复制标题
DOI：
10.1074/jbc.ra119.011932
复制
发表时间：
2020-05-15
影响因子：
4.8
通讯作者：
Sugita, Masahiko
中科院分区：
文献类型：
--
作者：
Shima, Yoko;Morita, Daisuke;Sugita, Masahiko
新合成的主要组织相容性复合体（MHC）I类蛋白的稳定在内质网（ER）的结合8？由抗原加工相关转运蛋白（TAP）提供的10聚体长的自身肽抗原。这些MHC I类：肽复合物然后离开ER并到达质膜，用于维持细胞表面上的稳态MHC I类表达。最近发现了一种新的MHC I类分子亚群，它优先结合含脂质的配体而不是传统的肽。灵长类经典的MHC I类同种异型物Mamu-B*098和Mamu-B*05104能够分别结合来源于N-豆蔻酰化的SIV Nef蛋白的N-豆蔻酰化的5-mer（C14-Gly-Gly-Ala-Ile-Ser）或4-mer（C14-Gly-Gly-Ala-Ile）脂肽，并激活脂肽抗原特异性细胞毒性T淋巴细胞。我们在此证明，Mamu-B*098样品溶血磷脂酰乙醇胺和溶血磷脂酰胆碱含有高达C20脂肪酸的ER。与溶血磷脂复合的Mamu-B *098和Mamu-B *05104的高分辨率X射线晶体结构显示，这些MHC I类分子的抗原结合凹槽中的B和D口袋通过单酰基甘油部分容纳这些脂质。与结合细胞脂质配体的能力一致，这两种MHC I类分子不需要TAP功能用于细胞表面表达。总的来说，这些结果表明，肽和脂肽呈递的MHC I类亚群使用不同来源的内源性配体。
Newly synthesized major histocompatibility complex (MHC) class I proteins are stabilized in the endoplasmic reticulum (ER) by binding 8?10-mer-long self-peptide antigens that are provided by transporter associated with antigen processing (TAP). These MHC class I:peptide complexes then exit the ER and reach the plasma membrane, serving to sustain the steady-state MHC class I expression on the cell surface. A novel subset of MHC class I molecules that preferentially bind lipid-containing ligands rather than conventional peptides was recently identified. The primate classical MHC class I allomorphs, Mamu-B*098 and Mamu-B*05104, are capable of binding the N-myristoylated 5-mer (C14-Gly-Gly-Ala-Ile-Ser) or 4-mer (C14-Gly-Gly-Ala-Ile) lipopeptides derived from the N-myristoylated SIV Nef protein, respectively, and of activating lipopeptide antigen-specific cytotoxic T lymphocytes. We herein demonstrate that Mamu-B*098 samples lysophosphatidylethanolamine and lysophosphatidylcholine containing up to a C20 fatty acid in the ER. The X-ray crystal structures of Mamu-B*098 and Mamu-B*05104 complexed with lysophospholipids at high resolution revealed that the B and D pockets in the antigen-binding grooves of these MHC class I molecules accommodate these lipids through a monoacylglycerol moiety. Consistent with the capacity to bind cellular lipid ligands, these two MHC class I molecules did not require TAP function for cell-surface expression. Collectively, these results indicate that peptide- and lipopeptide-presenting MHC class I subsets use distinct sources of endogenous ligands.