Department of Medicine, Division of Hematology, Sol Sherry Thrombosis Center, Temple University, Philadelphia, Pennsylvania, USA.
Curr Opin Hematol. 2018 Sep;25(5):395-402. doi: 10.1097/MOH.0000000000000449.
The present review provides an overview of recent findings on new members of the protein disulfide isomerase (PDI) family required for thrombosis.
Twenty years ago PDI was shown to mediate platelet aggregation, and 10 years ago PDI was shown to support thrombosis in vivo. Subsequently, other members of this endoplasmic reticulum family of enzymes, ERp57 and ERp5, were demonstrated to support thrombosis. A fourth member, ERp72, was recently shown to be required for platelet accumulation and fibrin deposition in vivo. None of these enzymes can individually support these processes. Moreover, aggregation of platelets deficient in a specific PDI is only recovered by the PDI that is missing. This implies that each PDI has a distinct role in activation of the αIIbβ3 fibrinogen receptor and platelet aggregation. Free thiols can be labeled in both subunits of αIIbβ3, suggesting cysteine-based reactions are involved in relaying conformational changes from the cytoplasmic tails to the integrin headpiece of this integrin.
Multiple members of the PDI family support platelet function, and hemostasis and thrombosis with distinct roles in these processes. The individual cysteine targets of each enzyme and how these enzymes are integrated into a network that supports hemostasis and thrombosis remain to be elucidated.
本综述概述了近年来关于蛋白质二硫键异构酶（PDI）家族新成员在血栓形成中的作用的最新发现。
20 年前，PDI 被证明能介导血小板聚集，10 年前，PDI 被证明能支持体内血栓形成。随后，该内质网酶家族的其他成员，ERp57 和 ERp5，也被证明能支持血栓形成。最近发现第四个成员 ERp72 是体内血小板聚集和纤维蛋白沉积所必需的。这些酶都不能单独支持这些过程。此外，缺乏特定 PDI 的血小板的聚集仅能被缺失的 PDI 恢复。这意味着每个 PDI 在激活 αIIbβ3 纤维蛋白原受体和血小板聚集中都有独特的作用。αIIbβ3 的两个亚基都可以用游离巯基标记，这表明基于半胱氨酸的反应参与了将构象变化从细胞质尾巴传递到该整合素的整联蛋白头部的过程。
PDI 家族的多个成员支持血小板功能和止血及血栓形成，在这些过程中具有不同的作用。每个酶的特定半胱氨酸靶标以及这些酶如何整合到支持止血和血栓形成的网络中仍有待阐明。
