Platelet glycoprotein lbα forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF
Platelet glycoprotein lbα forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF
复制标题
DOI：
10.1172/jci35754
复制
发表时间：
2008-09-01
影响因子：
15.9
通讯作者：
Zhu, Cheng
中科院分区：
文献类型：
--
作者：
Yago, Tadayuki;Lou, Jizhong;Zhu, Cheng
动脉血流增强糖蛋白Ib α。(GPIbα）与vWF结合，其启动血小板粘附至受损血管。导致2B型血管性血友病（vWD）的vWF A1结构域突变降低了粘附的血流需求。在这里，我们表明，GPIb α/vWF债券增加力首先延长（“捕捉”），然后缩短（“滑”）键寿命。两种2B型vWD Al结构域突变体R1306 Q和R1450 E通过在低力下延长键寿命将捕获键转化为滑动键。操纵分子动力学模拟GPIb α从Al结构域解离的建议机制捕获债券和它们的转换由Al结构域突变。随着流量从次优水平增加，捕获键导致血小板和GPIb α涂覆的微球在WT vWF和WT Al结构域上滚动得更慢，这解释了流量增强的滚动。在低力下较长的键寿命消除了在R1306 Q和R1450 E突变Al结构域上滚动的流动要求。流动的血小板与带有R1306 Q或R1450 E突变Al结构域但不带有WT Al结构域的微球凝集。因此，捕获键可以防止vWF多聚体凝集血小板。具有血小板反应蛋白1型基序-13（ADAMTS-13）的去整合素和金属蛋白酶以剪切依赖性方式降低了带有R1450 E突变的三结构域A1 A2 A3 vWF片段的微球的血小板凝集。我们得出结论，在2B型vWD中，循环血小板上GPIb α与vWF结合的寿命延长可能使ADAMTS-13耗尽大的vWF多聚体，导致出血。
Arterial blood flow enhances glycoprotein Ib alpha. (GPIb alpha) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIb alpha/vWF bonds first prolonged ("catch") and then shortened ("slip") bond lifetimes. Two type 2B vWD Al domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIb alpha dissociating from the Al domain suggested mechanisms for catch bonds and their conversion by the Al domain mutations. Catch bonds caused platelets and GPIb alpha-coated microspheres to roll more slowly on WT vWF and WT Al domains as flow increased from suboptimal levels, explaining flow-enhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant Al domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant Al domains, but not WT Al domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif-13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIb alpha on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding.