Holotoxin disassembly by protein disulfide isomerase is less efficient for Escherichia coli heat-labile enterotoxin than cholera toxin.
Holotoxin disassembly by protein disulfide isomerase is less efficient for Escherichia coli heat-labile enterotoxin than cholera toxin.
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DOI：
10.1038/s41598-021-03939-9
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发表时间：
2022-01-07
影响因子：
4.6
通讯作者：
Tatulian SA
中科院分区：
文献类型：
--
作者：
Serrano A;Guyette JL;Heim JB;Taylor M;Cherubin P;Krengel U;Teter K;Tatulian SA
霍乱毒素(CT)和大肠杆菌不耐热肠毒素(LT)是结构相似的AB5型蛋白毒素。它们从细胞表面移动到内质网，在那里A1催化亚基被蛋白质二硫键异构酶(PDI)从其全毒素中分离出来，从而允许解离的A1亚基进入胞浆产生毒性作用。尽管毒性机制相似，但CT比LT更有效。这种差异被归因于CT与LT相比有更稳定的结构域组装，但这一解释尚未得到直接检验，并有争议，因为毒素分解是这些毒素细胞作用中不可或缺的一步。我们在这里表明，PDI比LT更有效地分解CT，这为前一种毒素的更大效力提供了可能的解释。此外，对CT和LT结构域组件的直接检查在毒素稳定性方面没有发现差异。使用新的解析几何方法，我们提供了A亚基相对于B五聚体的位置的详细表征，并展示了CT和LT的结构域之间的显著差异。蛋白质对接分析进一步表明，这些全球结构差异导致了PDI-毒素相互作用的不同模式。我们的结果突出了以前被忽视的CT和LT之间的结构差异，这些差异为PDI辅助的分解和这些毒素的不同效力提供了一个新的模型。
Cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) are structurally similar AB5-type protein toxins. They move from the cell surface to the endoplasmic reticulum where the A1 catalytic subunit is separated from its holotoxin by protein disulfide isomerase (PDI), thus allowing the dissociated A1 subunit to enter the cytosol for a toxic effect. Despite similar mechanisms of toxicity, CT is more potent than LT. The difference has been attributed to a more stable domain assembly for CT as compared to LT, but this explanation has not been directly tested and is arguable as toxin disassembly is an indispensable step in the cellular action of these toxins. We show here that PDI disassembles CT more efficiently than LT, which provides a possible explanation for the greater potency of the former toxin. Furthermore, direct examination of CT and LT domain assemblies found no difference in toxin stability. Using novel analytic geometry approaches, we provide a detailed characterization of the positioning of the A subunit with respect to the B pentamer and demonstrate significant differences in the interdomain architecture of CT and LT. Protein docking analysis further suggests that these global structural differences result in distinct modes of PDI-toxin interactions. Our results highlight previously overlooked structural differences between CT and LT that provide a new model for the PDI-assisted disassembly and differential potency of these toxins.
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影响因子：
14.8
作者：
Kozakov D;Hall DR;Xia B;Porter KA;Padhorny D;Yueh C;Beglov D;Vajda S
通讯作者：
Vajda S
DOI：
10.1083/jcb.131.4.951
发表时间：
1995-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lencer WI;Constable C;Moe S;Jobling MG;Webb HM;Ruston S;Madara JL;Hirst TR;Holmes RK
通讯作者：
Holmes RK
DOI：
10.1016/j.bbapap.2017.08.014
发表时间：
2017-11
期刊：
Biochimica et biophysica acta. Proteins and proteomics
影响因子：
--
作者：
Freedman RB;Desmond JL;Byrne LJ;Heal JW;Howard MJ;Sanghera N;Walker KL;Wallis AK;Wells SA;Williamson RA;Römer RA
通讯作者：
Römer RA
影响因子：
3.7
作者：
Reddy S;Taylor M;Zhao M;Cherubin P;Geden S;Ray S;Francis D;Teter K
通讯作者：
Teter K
影响因子：
4
作者：
Cherubin, Patrick;Guyette, Jessica;Teter, Ken
通讯作者：
Teter, Ken