Crystal structure of HLA-DP2 and implications for chronic beryllium disease
Crystal structure of HLA-DP2 and implications for chronic beryllium disease
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DOI：
10.1073/pnas.1001772107
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发表时间：
2010-04-20
影响因子：
11.1
通讯作者：
Fontenot, Andrew P.
中科院分区：
文献类型：
--
作者：
Dai, Shaodong;Murphy, Guinevere A.;Fontenot, Andrew P.
慢性铍病（CBD）是一种由铍（Be）暴露引起的纤维化肺部疾病，其特征在于肉芽肿性炎症和Be反应性CD 4（+）T细胞在肺中的积聚。对CBD的遗传易感性与MHCII分子HLA-DP的某些等位基因相关，特别是HLA-DPB 1 *0201和在β链的位置69处含有谷氨酸残基的其他等位基因（β Glu 69）。可以将Be呈递给T细胞的HLA-DP等位基因与遗传易感性中涉及的等位基因相匹配，这表明HLA对疾病的贡献是基于这些分子结合并将Be呈递给T细胞的能力。HLA-DP 2的结构及其与Be的相互作用尚不清楚。在这里，我们提出了HLA-DP 2结构，其抗原结合沟被来自HLA-DR α链的自身肽占据。该结构最显著的特征是在肽骨架和HLA-DP 2 β链α-螺旋之间形成的不寻常的溶剂暴露酸性口袋，并且含有来自β链的三个谷氨酸，包括β Glu 69。在晶体包装中，这个口袋已经被来自相邻分子的精氨酸的胍基填充。这个带正电荷的部分与三个谷氨酸形成了广泛的H-键/盐桥网络，为含Be复合物如何占据该位点提供了一个合理的模型。这一想法得到了证实，即该口袋中的三种谷氨酸中的任何一种突变都会导致DP 2向T细胞呈递Be的能力丧失。
Chronic beryllium disease (CBD) is a fibrotic lung disorder caused by beryllium (Be) exposure and is characterized by granulomatous inflammation and the accumulation of Be-responsive CD4(+) T cells in the lung. Genetic susceptibility to CBD has been associated with certain alleles of the MHCII molecule HLA-DP, especially HLA-DPB1*0201 and other alleles that contain a glutamic acid residue at position 69 of the beta-chain (beta Glu69). The HLA-DP alleles that can present Be to T cells match those implicated in the genetic susceptibility, suggesting that the HLA contribution to disease is based on the ability of those molecules to bind and present Be to T cells. The structure of HLA-DP2 and its interaction with Be are unknown. Here, we present the HLA-DP2 structure with its antigen-binding groove occupied by a self-peptide derived from the HLA-DR alpha-chain. The most striking feature of the structure is an unusual solvent exposed acidic pocket formed between the peptide backbone and the HLA-DP2 beta-chain alpha-helix and containing three glutamic acids from the beta-chain, including beta Glu69. In the crystal packing, this pocket has been filled with the guanidinium group of an arginine from a neighboring molecule. This positively charged moiety forms an extensive H-bond/salt bridge network with the three glutamic acids, offering a plausible model for how Be-containing complexes might occupy this site. This idea is strengthened by the demonstration that mutation of any of the three glutamic acids in this pocket results in loss of the ability of DP2 to present Be to T cells.