The Intrinsically Disordered Domain of the Antitoxin Phd Chaperones the Toxin Doc against Irreversible Inactivation and Misfolding
The Intrinsically Disordered Domain of the Antitoxin Phd Chaperones the Toxin Doc against Irreversible Inactivation and Misfolding
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DOI：
10.1074/jbc.m114.572396
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发表时间：
2014-12-05
影响因子：
4.8
通讯作者：
Garcia-Pino, Abel
中科院分区：
文献类型：
--
作者：
De Gieter, Steven;Konijnenberg, Albert;Garcia-Pino, Abel
背景：doc/phd家族是毒素-抗毒素模块和蛋白质-蛋白质调节的一个范例。结果如下：没有Phd并且由于其不完整的Fic折叠，Doc是异质的并且易于聚集，并且可以在高浓度下在溶液中二聚化。结论：Phd作为抗聚集分子伴侣，保护毒素Doc免于错误折叠。重要性：抗毒素的内在无序结构域可以扩展蛋白质的功能。来自phd/doc毒素-抗毒素模块的毒素Doc靶向细胞翻译机器，并被其抗毒素配偶体Phd抑制。在这里，我们表明，博士也作为一个伴侣，保持博士在一个积极的，正确折叠的构象。在没有Phd的情况下，Doc以相对扩展的状态存在，其倾向于通过与其活性位点环作为铰链区的结构域交换而二聚化。结构域交换的二聚体不能在体外抑制蛋白质合成，而Doc单体则可以。在与Phd结合后，Doc变得更加紧凑，并通过中和的活性位点以其单体状态固定。
Background: The doc/phd family is a paradigm for toxin-antitoxin modules in particular and protein-protein regulation in general. Results: Without Phd and because of its incomplete Fic fold, Doc is heterogeneous and aggregation-prone and could dimerize in solution at high concentration. Conclusion: Phd acts as an antiaggregation chaperone, protecting the toxin Doc from misfolding. Significance: The intrinsically disordered domain of antitoxins can expand protein functionality.The toxin Doc from the phd/doc toxin-antitoxin module targets the cellular translation machinery and is inhibited by its antitoxin partner Phd. Here we show that Phd also functions as a chaperone, keeping Doc in an active, correctly folded conformation. In the absence of Phd, Doc exists in a relatively expanded state that is prone to dimerization through domain swapping with its active site loop acting as hinge region. The domain-swapped dimer is not capable of arresting protein synthesis in vitro, whereas the Doc monomer is. Upon binding to Phd, Doc becomes more compact and is secured in its monomeric state with a neutralized active site.