Dynamics of free versus complexed β2-microglobulin and the evolution of interfaces in MHC class I molecules
Dynamics of free versus complexed β2-microglobulin and the evolution of interfaces in MHC class I molecules
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DOI：
10.1007/s00251-012-0667-4
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发表时间：
2013-03-01
期刊：
影响因子：
3.2
通讯作者：
Ziegler, Andreas
中科院分区：
文献类型：
--
作者：
Hee, Chee-Seng;Beerbaum, Monika;Ziegler, Andreas
在主要组织相容性复合体（MHC）I类分子中，单态β（2）-微球蛋白（β（2）m）与表现出可变多态性程度的重链（HC）非共价结合。β M-2可以稳定从经典肽结合到非经典脂质呈递MHC I类分子以及不结合小配体的MHC I类样分子的多种复合物。在这里，我们的目标是评估在自由以及复杂的β（2）m的各个区域的动态，并了解β（2）m和不同的HC之间的接口的演变。使用人β 2 m和HLA-B*27：09复合物作为模型系统，首先通过核磁共振光谱进行游离和HC结合的β 2 m的比较。尽管某些区域在复合物形成后仍保持其柔性，但这些研究表明，β 2 m的大部分在与HC结合后获得刚性。序列分析表明，一些表现出灵活性的残基参与进化上保守的β（2）m-HC接触，这在不同的脊椎动物物种中是可检测的，或表征一组特定的MHC I类复合物，如肽或脂质结合分子。因此，光谱实验和界面分析表明，β（2）m不仅通过参与保守的分子间接触，而且通过依赖于表现出高度灵活性的关键界面残基，实现了与不同的MHC I类HC以及效应细胞受体相互作用的作用。
In major histocompatibility complex (MHC) class I molecules, monomorphic beta(2)-microglobulin (beta(2)m) is non-covalently bound to a heavy chain (HC) exhibiting a variable degree of polymorphism. beta M-2 can stabilize a wide variety of complexes ranging from classical peptide binding to nonclassical lipid presenting MHC class I molecules as well as to MHC class I-like molecules that do not bind small ligands. Here we aim to assess the dynamics of individual regions in free as well as complexed beta(2)m and to understand the evolution of the interfaces between beta(2)m and different HC. Using human beta(2)m and the HLA-B*27:09 complex as a model system, a comparison of free and HC-bound beta(2)m by nuclear magnetic resonance spectroscopy was initially carried out. Although some regions retain their flexibility also after complex formation, these studies reveal that most parts of beta(2)m gain rigidity upon binding to the HC. Sequence analyses demonstrate that some of the residues exhibiting flexibility participate in evolutionarily conserved beta(2)m-HC contacts which are detectable in diverse vertebrate species or characterize a particular group of MHC class I complexes such as peptide-or lipid-binding molecules. Therefore, the spectroscopic experiments and the interface analyses demonstrate that beta(2)m fulfills its role of interacting with diverse MHC class I HC as well as effector cell receptors not only by engaging in conserved intermolecular contacts but also by falling back upon key interface residues that exhibit a high degree of flexibility.