Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor
Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor
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DOI：
10.1073/pnas.0431098100
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发表时间：
2003-04-29
影响因子：
11.1
通讯作者：
Young, JAT
中科院分区：
文献类型：
--
作者：
Scobie, HM;Rainey, GJA;Young, JAT
炭疽芽孢杆菌分泌两种二组分毒素，被认为与炭疽病的发病和导致宿主死亡有关。目前的中毒模型是保护性抗原(PA)毒素亚基与一组细胞表面炭疽毒素受体(ATRs)结合，该受体由肿瘤内皮标记8(TEM8)基因编码。ATR/TEM8-PA的相互作用是由受体的胞外结构域(与von Willebrand因子A型或整合素插入结构域(vWA/I结构域)相关)介导的。位于ATR/TEM8蛋白这一结构域中的金属离子依赖的粘附点(MIDAS)可以螯合对PA结合至关重要的二价阳离子。在这份报告中，我们发现了由毛细血管形态发生基因2(CMG2)编码的第二个PA受体，它与VWA/I结构域中的ATR/TEM8有60%的氨基酸同源性，以及一个保守的MIDAS基序。当在受体缺陷的细胞上表达时，重组CMG2蛋白与PA结合并介导毒素内化。CMG2 VWA/I结构域与PA之间的结合是直接的和Meta I依赖的，尽管这种相互作用的阳离子特异性不同于ATR/TEM8。Northern印迹分析表明，CMG2在人体组织中广泛表达，表明该受体可能与疾病的发病机制有关。最后，当CMG2 VWA/I结构域以3：1的比例加入PA时，其可溶性版本可抑制表达内源性毒素受体的细胞的中毒。这些研究将CMG2区分为第二种炭疽毒素受体，并确定了一种可能被证明对炭疽病治疗有用的有效抗毒素。
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 ATR/TEM8-PA interaction is mediated by the receptor's extracellular domain related to von Willebrand factor type A or integrin inserted domains (VWA/I domains). A metal ion-dependent adhesion site (MIDAS) located within this domain of the ATR/TEM8 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 ATR/TEM8 within the VWA/I 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 VWA/I domain and PA was shown to be direct and meta I-dependent, although the cation specificity of this interaction is different than that observed with ATR/TEM8. 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 VWA/I 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.