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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor.
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Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor.

机译：人毛细血管形态发生蛋白2充当炭疽毒素受体。

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摘要

Bacillus anthracis secretes two bipartite toxins thought to be involved in anthrax pathogenesis and resulting death of the host. The current model for intoxication is that protective antigen (PA) toxin subunits bind a single group of cell-surface anthrax toxin receptors (ATRs), encoded by the tumor endothelial marker 8 (TEM8) gene. The ATRTEM8-PA interaction is mediated by the receptor's extracellular domain related to von Willebrand factor type A or integrin inserted domains (VWAI domains). A metal ion-dependent adhesion site (MIDAS) located within this domain of the ATRTEM8 protein chelates a divalent cation critical for PA binding. In this report, we identify a second PA receptor encoded by capillary morphogenesis gene 2 (CMG2), which has 60% amino acid identity to ATRTEM8 within the VWAI domain, as well as a conserved MIDAS motif. A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. Binding between the CMG2 VWAI domain and PA was shown to be direct and metal-dependent, although the cation specificity of this interaction is different than that observed with ATRTEM8. Northern blot analysis revealed that CMG2 is widely expressed in human tissues, indicating that this receptor is likely to be relevant for disease pathogenesis. Finally, a soluble version of the CMG2 VWAI domain inhibited intoxication of cells expressing endogenous toxin receptors when it was added to PA at a 3:1 ratio. These studies distinguish CMG2 as a second anthrax toxin receptor and identify a potent antitoxin that may prove useful for the treatment of anthrax.
机译：炭疽芽孢杆菌分泌两种被认为参与炭疽病发病机理并导致宿主死亡的二联毒素。当前的中毒模型是保护性抗原（PA）毒素亚基结合由肿瘤内皮标记8（TEM8）基因编码的单组细胞表面炭疽毒素受体（ATR）。 ATRTEM8-PA相互作用是由与von Willebrand因子A型或整联蛋白插入结构域（VWAI结构域）相关的受体胞外结构域介导的。位于ATRTEM8蛋白质此域内的金属离子依赖性粘附位点（MIDAS）螯合了对PA结合至关重要的二价阳离子。在此报告中，我们确定了由毛细管形态发生基因2（CMG2）编码的第二个PA受体，该受体与VWAI域内的ATRTEM8具有60％的氨基酸同一性，以及一个保守的MIDAS基序。当在受体缺陷细胞上表达时，重组CMG2蛋白结合PA并介导毒素内在化。 CMG2 VWAI结构域和PA之间的结合被证明是直接的并且是金属依赖性的，尽管这种相互作用的阳离子特异性不同于ATRTEM8所观察到的。 Northern印迹分析显示CMG2在人组织中广泛表达，表明该受体可能与疾病发病机理有关。最后，当将CMG2 VWAI域的可溶性形式以3：1的比例添加到PA中时，它会抑制表达内源性毒素受体的细胞中毒。这些研究将CMG2区分为第二种炭疽毒素受体，并确定了可能被证明对治疗炭疽有用的有效抗毒素。

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