HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution
HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution
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DOI：
10.1016/j.jmb.2007.12.009
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发表时间：
2008-02-22
影响因子：
5.6
通讯作者：
Naumann, Dieter
中科院分区：
文献类型：
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作者：
Febian, Heinz;Huser, Hans;Naumann, Dieter
人类白细胞抗原(HLAI)类分子由重链、β(2)-微球蛋白和非共价结合的多肽组成。某些人类白细胞抗原-B27亚型与强直性脊柱炎相关(如：人类白细胞抗原-B*2705)，而其他亚型(如：人类白细胞抗原-B*2709)与强直性脊柱炎无关。两者在容纳多肽C末端的F口袋中只有一个残基(分别为Asp116和His116)不同。对这些HLA-B27亚型与自体多肽RRKWRRWHL的结合进行了同位素编辑红外光谱研究，结果表明，与自身多肽RRKWRWHL相比，HLA-B*2705的重链更具柔韧性。与这些实验数据一致的是，分子动力学模拟显示，与人类白细胞抗原-B*2709亚型相比，人类白细胞抗原-B*2705结合槽具有更高的灵活性。这种差异与人类白细胞抗原-B*2705结合槽的打开有关，伴随着C端肽锚的部分脱落。这些联合结果表明，深度嵌入的多态重链残基116如何以一种亚型依赖的方式影响肽结合槽的灵活性，这一特征也可能影响效应细胞对HLA-B27复合体的识别。(C)2007爱思唯尔有限公司。保留所有权利。
Human leukocyte antigen (HLA) class I molecules consist of a heavy chain, beta(2)-microglobulin, and a peptide that are noncovalently bound. Certain HLA-B27 subtypes are associated with ankylosing spondylitis (such as HLA-B*2705), whereas others (such as HLA-B*2709) are not. Both differ in only one residue (Asp116 and His116, respectively) in the F pocket that accommodates the peptide C-terminus. An isotope-edited IR spectroscopy study of these HLA-B27 subtypes complexed with the self-peptide RRKWRRWHL was carried out, revealing that the heavy chain is more flexible in the HLA-B*2705 than in the HLA-B*2709 subtype. In agreement with these experimental data, molecular dynamics simulations showed an increased flexibility of the HLA-B*2705 binding groove in comparison with that of the HLA-B*2709 subtype. This difference correlates with an opening of the HLA-B*2705 binding groove, accompanied by a partial detachment of the C-terminal peptide anchor. These combined results demonstrate how the deeply embedded polymorphic heavy-chain residue 116 influences the flexibility of the peptide binding groove in a subtype-dependent manner, a feature that could also influence the recognition of the HLA-B27 complexes by effector cells. (C) 2007 Elsevier Ltd. All rights reserved.