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Nature:炭疽霉素的作用机制

摘要 : 炭疽霉素利用其保护性抗原(PA)成分来在核内体膜中形成小孔,以便将其酶成分、 致死因子和水肿因子转位到目标细胞内。

 炭疽霉素利用其保护性抗原(PA)成分来在核内体膜中形成小孔,以便将其酶成分、 致死因子和水肿因子转位到目标细胞内。Hong Zhou及同事利用低温电子显微镜以2.9 Å这个很高的分辨率确定了PA孔的结构。该结构显示了人们长期寻找的催化性“Φ-clamp”或“苯基丙氨酸 clamp”和跨膜转位通道,并且支持关于蛋白转位的一个“布朗棘轮模型”。

原文链接:

Atomic structure of anthrax protective antigen pore elucidates toxin translocation

原文摘要:

Anthrax toxin, comprising protective antigen, lethal factor, and oedema factor, is the major virulence factor of Bacillus anthracis, an agent that causes high mortality in humans and animals. Protective antigen forms oligomeric prepores that undergo conversion to membrane-spanning pores by endosomal acidification, and these pores translocate the enzymes lethal factor and oedema factor into the cytosol of target cells. Protective antigen is not only a vaccine component and therapeutic target for anthrax infections but also an excellent model system for understanding the mechanism of protein translocation. On the basis of biochemical and electrophysiological results, researchers have proposed that a phi (Φ)-clamp composed of phenylalanine (Phe)427 residues of protective antigen catalyses protein translocation via a charge-state-dependent Brownian ratchet. Although atomic structures of protective antigen prepores are available, how protective antigen senses low pH, converts to active pore, and translocates lethal factor and oedema factor are not well defined without an atomic model of its pore. Here, by cryo-electron microscopy with direct electron counting, we determine the protective antigen pore structure at 2.9-Å resolution. The structure reveals the long-sought-after catalytic Φ-clamp and the membrane-spanning translocation channel, and supports the Brownian ratchet model for protein translocation. Comparisons of four structures reveal conformational changes in prepore to pore conversion that support a multi-step mechanism by which low pH is sensed and the membrane-spanning channel is formed.

来源: Nature 浏览次数:0

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