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首页> 美国卫生研究院文献>The Journal of Experimental Medicine >Evidence That the Autoimmune Antigen Myelin Basic Protein (MBP) Ac1-9 Binds Towards One End of the Major Histocompatibility Complex (MHC) Cleft
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Evidence That the Autoimmune Antigen Myelin Basic Protein (MBP) Ac1-9 Binds Towards One End of the Major Histocompatibility Complex (MHC) Cleft

机译：自身免疫抗原髓鞘碱性蛋白（MBP）Ac1-9结合到主要组织相容性复合体（MHC）的一端的证据

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The NH2-terminal peptide of myelin basic protein (MBP) bound to the class II major histocompatibility complex (MHC) protein I-Au is an immunodominant epitope in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. However, the MBP–I-Au complex is very unstable. To investigate this, we performed site-directed mutagenesis of the I-Au MHC protein and the MBP peptide. Biochemical, T cell activation, and molecular modeling studies of mutant complexes demonstrate that the MBP peptide's key residue for MHC binding, lysine 4, is buried in the P6 pocket of I-Au, which is predominantly hydrophobic. This implies that the MBP–I-Au complex differs from more stable complexes in two respects: (a) the peptide leaves the NH2-terminal region of the MHC peptide-binding cleft unoccupied; (b) the peptide is not anchored by typical favorable interactions between peptide side chains and MHC pockets. To test these hypotheses, a modified MBP peptide was designed based on molecular modeling, with the aim of producing strong I-Au binding. Extension of the NH2 terminus of MBP with six amino acids from the ova peptide, and replacement of the lysine side chain in the P6 pocket with an aromatic anchor, results in >1,000-fold increased binding stability. These results provide an explanation for the unusual peptide–MHC-binding kinetics of MBP, and should facilitate an understanding of why mice are not tolerant to this self-peptide– MHC complex.
机译：髓鞘碱性蛋白（MBP）的NH2末端肽与II类主要组织相容性复合物（MHC）蛋白I-A u 结合，是实验性自身免疫性脑脊髓炎（一种多发性硬化的小鼠模型）中的免疫优势表位。但是，MBP–I-A u 复合物非常不稳定。为了对此进行研究，我们对I-A u MHC蛋白和MBP肽进行了定点诱变。突变体复合物的生化，T细胞活化和分子建模研究表明，MBP肽与MHC结合的关键残基赖氨酸4被掩埋在I-A u 的P6口袋中，该口袋主要是疏水性的。这意味着MBP–I-A u 复合物在两个方面与更稳定的复合物不同：（a）肽空置了MHC肽结合裂隙的NH2末端区域； （b）肽没有被肽侧链和MHC口袋之间的典型有利相互作用所锚定。为了验证这些假设，基于分子模型设计了修饰的MBP肽，目的是产生强烈的I-A u 结合。用ova肽中的6个氨基酸扩展MBP的NH2末端，并用芳香族锚定取代P6口袋中的赖氨酸侧链，导致结合稳定性提高> 1,000倍。这些结果为MBP的异常的多肽-MHC结合动力学提供了解释，并且应该有助于理解为什么小鼠不耐受这种自身肽-MHC复合物。

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