Membrane-Binding Mechanism of Clostridium perfringens Alpha-Toxin.
Membrane-Binding Mechanism of Clostridium perfringens Alpha-Toxin.
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DOI：
10.3390/toxins7124880
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发表时间：
2015-12-03
期刊：
影响因子：
4.2
通讯作者：
Nagahama M
中科院分区：
文献类型：
--
作者：
Oda M;Terao Y;Sakurai J;Nagahama M
产气荚膜梭菌α-毒素是气性坏疽的关键介质，气性坏疽是一种威胁生命的感染，表现为发热、疼痛、浮肿、肌坏死和产气。α-毒素具有磷脂酶C和鞘磷脂酶活性。该毒素由一个N-末端结构域(1-250个氨基酸，N-结构域)和一个C-末端结构域(251-370个氨基酸，C-结构域)组成，C-末端结构域是膜结合部位。用C区免疫小鼠可以预防产气荚膜梭菌引起的气性坏疽，而用N区免疫则没有效果。中央环区(55-93 aa)，特别是H….SW84Y85…在与神经节苷脂GM1a的相互作用中起着重要作用。该毒素在GM1a/TrkA复合体存在的情况下与脂筏结合，并通过α-毒素本身的酶活性与从磷脂酰胆碱到二酰甘油的代谢产物结合。这些膜动力学导致内源性PLCγ-1通过TrkA被激活。此外，在神经节苷脂缺乏的DOQ细胞中，用α-毒素处理会导致膜筏上形成二酰甘油；这反过来又会触发内吞和细胞死亡。本文对目前α-毒素的膜结合机制进行了详细的综述。
Clostridium perfringens alpha-toxin is a key mediator of gas gangrene, which is a life-threatening infection that manifests as fever, pain, edema, myonecrosis, and gas production. Alpha-toxin possesses phospholipase C and sphingomyelinase activities. The toxin is composed of an N-terminal domain (1–250 aa, N-domain), which is the catalytic site, and a C-terminal domain (251–370 aa, C-domain), which is the membrane-binding site. Immunization of mice with the C-domain of alpha-toxin prevents the gas gangrene caused by C. perfringens, whereas immunization with the N-domain has no effect. The central loop domain (55–93 aa), especially H….SW84Y85….G, plays an important role in the interaction with ganglioside GM1a. The toxin binds to lipid rafts in the presence of a GM1a/TrkA complex, and metabolites from phosphatidylcholine to diacylglycerol through the enzymatic activity of alpha-toxin itself. These membrane dynamics leads to the activation of endogenous PLCγ-1 via TrkA. In addition, treatment with alpha-toxin leads to the formation of diacylglycerol at membrane rafts in ganglioside-deficient DonQ cells; this in turn triggers endocytosis and cell death. This article summarizes the current the membrane-binding mechanism of alpha-toxin in detail.