INHIBITION OF A REDUCTIVE FUNCTION OF THE PLASMA-MEMBRANE BY BACITRACIN AND ANTIBODIES AGAINST PROTEIN DISULFIDE-ISOMERASE
INHIBITION OF A REDUCTIVE FUNCTION OF THE PLASMA-MEMBRANE BY BACITRACIN AND ANTIBODIES AGAINST PROTEIN DISULFIDE-ISOMERASE
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DOI：
10.1073/pnas.90.9.4112
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发表时间：
1993-05-01
影响因子：
11.1
通讯作者：
PEAK, D
中科院分区：
文献类型：
--
作者：
MANDEL, R;RYSER, HJP;PEAK, D
有证据表明，二硫键连接的[I-125]碘酪胺/聚(D-赖氨酸)偶联物在非特异性结合到中国仓鼠卵巢(CHO)细胞表面时被还原切割，这种切割被膜上非特异性的巯基阻断剂取消。随后发现相同的阻断剂可以抑制白喉毒素的细胞毒性，白喉毒素是一种二硫键连接的异二聚体，与特定的表面受体结合，必须经过链分离才能发挥其细胞毒性。这表明这两个大分子的二硫键可能是由蛋白质二硫键异构酶(PDI，EC 5.3.4.1)介导的硫醇-二硫键交换反应。我们测试了PDI的抑制剂--尤其是杆菌肽和抗PDI抗体--是否可以模仿巯基阻滞剂的两种作用。杆菌肽和抗PDI抗体都能有效地抑制这两种还原过程。这有力地表明，这两个膜结合的大分子中的二硫键裂解是由PDI介导的，这种酶除了已知保留在内质网外，还必须暴露在质膜上。这篇论文指出了可能由表面相关的PDI催化的其他潜在的重要的二硫化物还原。因此，它拓宽了一种已知的多功能酶的功能。
Evidence had been provided that a disulfide-linked [I-125]iodotyramine/poly(D-lysine) conjugate was reductively cleaved when bound nonspecifically to the surface of Chinese hamster ovary (CHO) cells and that this cleavage was abolished by membrane-impermeant sulfhydryl blockers. The same blockers were subsequently found to inhibit the cytotoxicity of diphtheria toxin, a disulfide-linked heterodimer that binds to a specific surface receptor and must undergo chain separation to exert its cytotoxicity. This suggested that the disulfides of both macromolecules might be cleaved by a thiol-disulfide interchange reaction, possibly mediated by protein disulfide-isomerase (PDI, EC 5.3.4.1). We tested whether inhibitors of PDI-in particular, bacitracin and anti-PDI antibodies-might mimic the two effects of sulfhydryl blockers. Both bacitracin and anti-PDI antibodies were effective in inhibiting both reductive processes. This strongly suggests that the disulfide cleavage in the two membrane-bound macromolecules is mediated by PDI and that this enzyme, besides its known retention in the endoplasmic reticulum, must also be exposed at the plasma membrane. This paper points to other potentially important disulfide reductions that might be catalyzed by surface-associated PDI. It thereby broadens the known functions of an enzyme already known for its multifunctional properties.