Flaumenhaft Robert, Furie Bruce
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Blood. 2016 Aug 18;128(7):893-901. doi: 10.1182/blood-2016-04-636456. Epub 2016 Jun 29.
Thiol isomerases are multifunctional enzymes that influence protein structure via their oxidoreductase, isomerase, and chaperone activities. These enzymes localize at high concentrations in the endoplasmic reticulum of all eukaryotic cells where they serve an essential function in folding nascent proteins. However, thiol isomerases can escape endoplasmic retention and be secreted and localized on plasma membranes. Several thiol isomerases including protein disulfide isomerase, ERp57, and ERp5 are secreted by and localize to the membranes of platelets and endothelial cells. These vascular thiol isomerases are released following vessel injury and participate in thrombus formation. Although most of the activities of vascular thiol isomerases that contribute to thrombus formation are yet to be defined at the molecular level, allosteric disulfide bonds that are modified by thiol isomerases have been described in substrates such as αIIbβ3, αvβ3, GPIbα, tissue factor, and thrombospondin. Vascular thiol isomerases also act as redox sensors. They respond to the local redox environment and influence S-nitrosylation of surface proteins on platelets and endothelial cells. Despite our rudimentary understanding of the mechanisms by which thiol isomerases control vascular function, the clinical utility of targeting them in thrombotic disorders is already being explored in clinical trials.
硫醇异构酶是多功能酶，通过其氧化还原酶、异构酶和伴侣活性影响蛋白质结构。这些酶在所有真核细胞的内质网中高浓度定位，在新生蛋白质折叠中发挥重要作用。然而，硫醇异构酶可逃避内质网滞留，分泌并定位在质膜上。包括蛋白质二硫键异构酶、ERp57和ERp5在内的几种硫醇异构酶由血小板和内皮细胞膜分泌并定位于这些膜上。这些血管硫醇异构酶在血管损伤后释放，参与血栓形成。尽管血管硫醇异构酶促进血栓形成的大多数活性在分子水平上尚未明确，但硫醇异构酶修饰的变构二硫键已在诸如αIIbβ3、αvβ3、糖蛋白Ibα、组织因子和血小板反应蛋白等底物中得到描述。血管硫醇异构酶还充当氧化还原传感器。它们对局部氧化还原环境作出反应，并影响血小板和内皮细胞表面蛋白的S-亚硝基化。尽管我们对硫醇异构酶控制血管功能的机制了解尚浅，但在血栓性疾病中靶向它们的临床应用价值已在临床试验中得到探索。
