Insight Into Pathological Integrin αIIbβ3 Activation From Safeguarding The Inactive State.
Insight Into Pathological Integrin αIIbβ3 Activation From Safeguarding The Inactive State.
复制标题
从保护非活动状态洞察病理性整合素αIIbβ3 激活。
DOI：
10.1016/j.jmb.2021.166832
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发表时间：
2021
影响因子：
5.6
通讯作者：
Ulmer,TobiasS
中科院分区：
文献类型：
--
作者：
Situ,AlanJ;Kim,Jiyoon;An,Woojin;Kim,Chungho;Ulmer,TobiasS
抑制血小板粘附受体整合素αIIbβ3的生理活化途径可能无法预防致命性血栓形成，表明该受体存在通过尚未鉴定的途径活化的风险。在这里，我们报告的发现和表征的结构基序，保护受体的选择性地破坏其非活性状态。在细胞外膜边缘，过度包装的αIIb（W 968）-β3（I693）接触阻止αIIb（Gly 972）最佳组装αIIbβ3跨膜复合物，从而维持非活性状态。这种约1.0 kcal/mol的不稳定性可以通过流体动力而不是生理激动剂来减轻，从而将流体动力鉴定为病理激活刺激。由于生殖寿命通常不受心血管疾病的限制，因此该保护措施的演变似乎是由健康心血管系统中致命的、流体动力介导的整合素αIIbβ3激活驱动的。仅通过病理刺激触发保护措施实现了非活性和活性受体状态之间的自由能屏障的有效增加，而不会导致出血风险的增加。因此，整合素αIIbβ3已经进化出一种保护受体功能状态的有效方式，这表明当流体动力超过生理界限时，机械活化途径的可用性。
The inhibition of physiological activation pathways of the platelet adhesion receptor integrin αIIbβ3 may fail to prevent fatal thrombosis, suggesting that the receptor is at risk of activation by yet an unidentified pathway. Here, we report the discovery and characterization of a structural motif that safeguards the receptor by selectively destabilizing its inactive state. At the extracellular membrane border, an overpacked αIIb(W968)-β3(I693) contact prevents αIIb(Gly972) from optimally assembling the αIIbβ3 transmembrane complex, which maintains the inactive state. This destabilization of approximately 1.0 kcal/mol could be mitigated by hydrodynamic forces but not physiological agonists, thereby identifying hydrodynamic forces as pathological activation stimulus. As reproductive life spans are not generally limited by cardiovascular disease, it appears that the evolution of the safeguard was driven by fatal, hydrodynamic force-mediated integrin αIIbβ3 activation in the healthy cardiovascular system. The triggering of the safeguard solely by pathological stimuli achieves an effective increase of the free energy barrier between inactive and active receptor states without incurring an increased risk of bleeding. Thus, integrin αIIbβ3 has evolved an effective way to protect receptor functional states that indicates the availability of a mechanical activation pathway when hydrodynamic forces exceed physiological margins.