A receptor-based switch that regulates anthrax toxin pore formation.
A receptor-based switch that regulates anthrax toxin pore formation.
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DOI：
10.1371/journal.ppat.1002354
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Young JA
中科院分区：
文献类型：
--
作者：
Pilpa RM;Bayrhuber M;Marlett JM;Riek R;Young JA
细胞受体可以充当分子开关，调节微生物蛋白质对促进细胞进入的构象变化的敏感性。这些基于受体的开关的活动仅部分了解。在本文中，我们试图了解ANTXR 2炭疽毒素受体为基础的开关，结合保护性抗原（PA）毒素亚基的结构域2和4的活性的机制。受体结合限制了七聚体PA前孔内的结构变化，这些结构变化是孔转化为酸性内体隔室所需的。转移交叉饱和（TCS）NMR方法被用来监测在不同的步骤在prepore-to-pore转换的七聚体PA-受体接触的变化。这些研究表明，受体与PA结构域2的接触在孔转化之前减弱，从而在该途径中定义了一种新的中间体。重要的是，ANTXR 2在孔转化后仍然与PA结构域4结合，表明结合的受体可能影响新形成的孔的结构和/或功能。这些研究为控制炭疽毒素进入细胞的基于受体的分子开关的功能提供了新的见解。引起炭疽的细菌产生一种称为炭疽毒素的毒素，这种毒素是引起疾病症状的主要原因。炭疽中毒的第一步涉及毒素与细胞表面上一种称为受体的特定蛋白质结合。受体结合就像一个开关，防止毒素在细胞膜上形成一个孔，直到毒素-受体复合物被吸收到细胞中并被递送到一个特定的位置（称为内体），在那里它暴露于“酸浴”。这种酸性环境促进毒素的结构变化，导致内体膜中的孔形成。在这份报告中，我们研究了受体如何调节孔形成以下相关的变化，毒素受体接触。这些研究已经确定了导致孔转化的途径中的新的毒素-受体中间体，并且证明了受体在孔转化后保持结合。我们的研究结果为受体如何调节炭疽毒素孔的形成提供了重要的新见解，这些信息可能有助于设计治疗这种疾病的新治疗策略。
Cellular receptors can act as molecular switches, regulating the sensitivity of microbial proteins to conformational changes that promote cellular entry. The activities of these receptor-based switches are only partially understood. In this paper, we sought to understand the mechanism that underlies the activity of the ANTXR2 anthrax toxin receptor-based switch that binds to domains 2 and 4 of the protective antigen (PA) toxin subunit. Receptor-binding restricts structural changes within the heptameric PA prepore that are required for pore conversion to an acidic endosomal compartment. The transfer cross-saturation (TCS) NMR approach was used to monitor changes in the heptameric PA-receptor contacts at different steps during prepore-to-pore conversion. These studies demonstrated that receptor contact with PA domain 2 is weakened prior to pore conversion, defining a novel intermediate in this pathway. Importantly, ANTXR2 remained bound to PA domain 4 following pore conversion, suggesting that the bound receptor might influence the structure and/or function of the newly formed pore. These studies provide new insights into the function of a receptor-based molecular switch that controls anthrax toxin entry into cells. The bacterium that causes anthrax produces a toxin called anthrax toxin that is largely responsible for causing disease symptoms. The first step in anthrax intoxication involves binding of the toxin to a specific protein, called a receptor, on the cell surface. Receptor-binding acts like a switch to prevent the toxin from forming a pore in a cell membrane until the toxin-receptor complex is taken up into cells and delivered to a specific location (called an endosome) where it is exposed to an “acid bath”. This acidic environment promotes structural changes in the toxin leading to pore formation in the endosomal membrane. In this report, we have studied how the receptor regulates pore formation by following the associated changes in toxin-receptor contacts. These studies have defined a new toxin-receptor intermediate in the pathway leading to pore conversion and demonstrate that the receptor remains bound after pore conversion. Our results provide important new insights into how the receptor regulates anthrax toxin pore formation, information that could be useful for designing new therapeutic strategies to treat this disease.
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影响因子：
16.8
作者：
通讯作者：
--
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
2.9
作者：
Miller, CJ;Elliott, JL;Collier, RJ
通讯作者：
Collier, RJ
DOI：
10.1073/pnas.79.10.3162
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
LEPPLA, SH
通讯作者：
LEPPLA, SH
DOI：
10.1073/pnas.0501864102
发表时间：
2005-06-14
影响因子：
11.1
作者：
Melikyan, GB;Barnard, RJO;Young, JAT
通讯作者：
Young, JAT