pH stability of HLA-DR4 complexes with antigenic peptides
pH stability of HLA-DR4 complexes with antigenic peptides
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DOI：
10.1021/bi001544g
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发表时间：
2000-11-28
期刊：
影响因子：
2.9
通讯作者：
McConnell, HM
中科院分区：
文献类型：
--
作者：
Belmares, MP;Rabinowitz, JD;McConnell, HM
抗原肽和主要组织相容性复合物 (MHC) 的 II 类蛋白之间的复合物会触发细胞免疫反应。与在细胞表面发挥作用的中性 pH 值相比，这些复合物在细胞内形成的弱酸性 pH 值下通常解离得更快。本文描述了 MHC 蛋白与含有天冬氨酸和谷氨酸残基的抗原肽之间的复合物解离动力学的 pH 依赖性。其中一些复合物表现出不寻常的 pH 依赖性，在 pH 7 时解离速度比在 pH 5.3 时解离速度快得多。当天冬氨酸或谷氨酸残基的羧酸根位于蛋白质的中性口袋中时，就会发生这种情况。相比之下，暴露于溶剂的羧酸盐基团或埋在口袋中与蛋白质形成盐桥的羧酸盐基团则没有表现出这种不寻常的pH依赖性。具有不寻常的pH依赖性的动力学数据密切符合模型，其中较不稳定的去质子化复合物和较稳定的质子化复合物之间存在快速可逆平衡。在此模型中，部分掩埋的肽羧酸酯基团的质子化反应的 pK(a) 范围为 7.7 至 8.3，反映了去质子化所需的强碱性条件。少数被证明在人类自身免疫中发挥作用的肽/MHC 复合物之一含有隐藏的肽羧酸盐，并显示出这种不寻常的 pH 依赖性。简要讨论了这一发现与理解自身免疫化学基础的相关性。
Complexes between antigenic peptides and class II proteins of the major histocompatibility complex (MHC) trigger cellular immune responses. These complexes usually dissociate more rapidly at mildly acidic pH, where they are formed intracellularly, as compared to neutral pH, where they function at the cell surface. This paper describes the pH dependence of the dissociation kinetics of complexes between MHC proteins and antigenic peptides containing aspartic and glutamic acid residues. Some of these complexes show an unusual pH dependence, dissociating much more rapidly at pH 7 than at pH 5.3. This occurs when the carboxylate group of the aspartic or glutamic acid residue is located in a neutral pocket of the protein. In contrast, solvent-exposed carboxylate groups or carboxylate groups buried in pockets where they form salt bridges with the protein do not show this unusual pH dependence. The kinetic data having the unusual pH dependence conform closely to a model in which there is a rapid reversible equilibration between a less stable deprotonated complex and a more stable protonated complex. In this model, the pK(a) of the protonation reaction for the partially buried peptide carboxylate group ranges from 7.7 to 8.3, reflecting the strongly basic conditions required for deprotonation. One of the few peptide/MHC complexes demonstrated to play a role in autoimmunity in humans contains a buried peptide carboxylate and shows this unusual pH dependence. The relevance of this finding to understanding the chemical basis of autoimmunity is briefly discussed.