Lee C, McConnell H M
Department of Chemistry, Stanford University, CA 94305, USA.
Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8269-73. doi: 10.1073/pnas.92.18.8269.
The binding of invariant chain to major histocompatibility complex (MHC) proteins is an important step in processing of MHC class II proteins and in antigen presentation. The question of how invariant chain can bind to all MHC class II proteins is central to understanding these processes. We have employed molecular modeling to predict the structure of class II-associated invariant chain peptide (CLIP)-MHC protein complexes and to ask whether the predicted mode of association could be general across all MHC class II proteins. CLIP fits identically into the MHC class II alleles HLA-DR3, I-Ak, I-Au, and I-Ad, with a consistent pattern of hydrogen bonds, contacts, and hydrophobic burial and without bad contacts. Our model predicts the burial of CLIP residues Met-91 and Met-99 in the deep P1 and P9 anchor pockets and other detailed interactions, which we have compared with available data. The predicted pattern of I-A allele-specific effects on CLIP binding is very similar to that observed experimentally by alanine-scanning mutations of CLIP. Together, these results indicate that CLIP may bind in a single, general way across products of MHC class II alleles.
恒定链与主要组织相容性复合体（MHC）蛋白的结合是MHC II类蛋白加工及抗原呈递过程中的重要步骤。恒定链如何能够结合所有MHC II类蛋白这一问题是理解这些过程的核心。我们利用分子建模来预测II类相关恒定链肽（CLIP）-MHC蛋白复合物的结构，并探究预测的结合模式是否对所有MHC II类蛋白都具有普遍性。CLIP以相同的方式适配于MHC II类等位基因HLA-DR3、I-Ak、I-Au和I-Ad，具有一致的氢键、接触及疏水埋藏模式且无不良接触。我们的模型预测CLIP残基Met-91和Met-99埋藏于深的P1和P9锚定口袋中以及其他详细的相互作用，我们已将其与现有数据进行比较。预测的I-A等位基因对CLIP结合的特异性效应模式与通过CLIP丙氨酸扫描突变实验观察到的模式非常相似。这些结果共同表明，CLIP可能以单一、普遍的方式结合于MHC II类等位基因的产物。
