Modulation of toxin stability by 4-phenylbutyric acid and negatively charged phospholipids.
Modulation of toxin stability by 4-phenylbutyric acid and negatively charged phospholipids.
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DOI：
10.1371/journal.pone.0023692
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Teter K
中科院分区：
文献类型：
--
作者：
Ray S;Taylor M;Burlingame M;Tatulian SA;Teter K
AB毒素如蓖麻毒素和霍乱毒素（CT）由酶促A结构域和受体结合B结构域组成。在表面结合的毒素被内吞后，蓖麻毒素和CT都被囊泡载体转运到内质网（ER）。然后A亚基从其全毒素中解离，展开并穿过ER膜到达其胞质靶标。由于蛋白质在生理温度和中性pH下展开允许解离的A链达到转运能力状态以出口到胞质溶胶，毒素展开的潜在调控机制具有重要的生物学意义。在这里，我们报告了一个生物物理分析的影响，阴离子磷脂膜和两个化学伴侣，4-苯基丁酸（PBA）和甘油，蓖麻毒素A链（RTA）和CTA 1链（CTA 1）的热稳定性和毒性效力。磷脂囊泡，模仿ER膜显着降低RTA的热稳定性，但不CTA 1。PBA和甘油均能抑制RTA的热无序，但只有甘油能逆转阴离子磷脂的失稳作用。与此相反，PBA是能够增加的热稳定性的CTA 1在阴离子磷脂的存在下。PBA抑制CT而不是蓖麻毒素的细胞中毒，这是通过其稳定CTA 1的能力和其无法逆转膜对RTA的不稳定作用来解释的。我们的数据突出了毒素特异性细胞内事件的基础ER到胞质转运的毒素A链，并确定了一种潜在的手段，以补充长期稳定的毒素疫苗。
AB toxins such as ricin and cholera toxin (CT) consist of an enzymatic A domain and a receptor-binding B domain. After endocytosis of the surface-bound toxin, both ricin and CT are transported by vesicle carriers to the endoplasmic reticulum (ER). The A subunit then dissociates from its holotoxin, unfolds, and crosses the ER membrane to reach its cytosolic target. Since protein unfolding at physiological temperature and neutral pH allows the dissociated A chain to attain a translocation-competent state for export to the cytosol, the underlying regulatory mechanisms of toxin unfolding are of paramount biological interest. Here we report a biophysical analysis of the effects of anionic phospholipid membranes and two chemical chaperones, 4-phenylbutyric acid (PBA) and glycerol, on the thermal stabilities and the toxic potencies of ricin toxin A chain (RTA) and CT A1 chain (CTA1). Phospholipid vesicles that mimic the ER membrane dramatically decreased the thermal stability of RTA but not CTA1. PBA and glycerol both inhibited the thermal disordering of RTA, but only glycerol could reverse the destabilizing effect of anionic phospholipids. In contrast, PBA was able to increase the thermal stability of CTA1 in the presence of anionic phospholipids. PBA inhibits cellular intoxication by CT but not ricin, which is explained by its ability to stabilize CTA1 and its inability to reverse the destabilizing effect of membranes on RTA. Our data highlight the toxin-specific intracellular events underlying ER-to-cytosol translocation of the toxin A chain and identify a potential means to supplement the long-term stabilization of toxin vaccines.
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影响因子：
2.9
作者：
Deeks, ED;Cook, JP;Lord, JM
通讯作者：
Lord, JM
影响因子：
4.8
作者：
Argent, RH;Parrott, AM;Radford, SE
通讯作者：
Radford, SE
DOI：
10.1074/jbc.m808387200
发表时间：
2009-04-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mayerhofer PU;Cook JP;Wahlman J;Pinheiro TT;Moore KA;Lord JM;Johnson AE;Roberts LM
通讯作者：
Roberts LM
DOI：
10.1016/j.bbamcr.2008.11.017
发表时间：
2009-03-01
影响因子：
5.1
作者：
Guerra, Lina;Nemec, Kathleen N.;Teter, Ken
通讯作者：
Teter, Ken
影响因子：
3.5
作者：
Majoul, I;Ferrari, D;Soling, HD
通讯作者：
Soling, HD