Integrin αIIbβ3 intermediates: From molecular dynamics to adhesion assembly
Integrin αIIbβ3 intermediates: From molecular dynamics to adhesion assembly
复制标题
整合素αIIbβ3中间体：从分子动力学到粘附组装
DOI：
10.1016/j.bpj.2022.12.032
复制
发表时间：
2023
影响因子：
3.4
通讯作者：
Bidone, Tamara C.
中科院分区：
文献类型：
--
作者：
Tong, Dudu;Soley, Nidhi;Kolasangiani, Reza;Schwartz, Martin A.;Bidone, Tamara C.
血小板整合素αIIbβ 3在止血过程中经历了与其从非活性（低亲和力）到活性（高亲和力）的功能转换相关的长程构象转变。虽然新的构象之间的良好的特征弯曲和扩展状态的中间已被确定，其分子动力学特性和功能在组装的粘连仍然在很大程度上未被探索。在这项研究中，我们评估了整合素αIIbβ 3的中间构象的性质，并通过结合全原子模拟，主成分分析和介观模拟来表征它们对粘附组装的影响。我们的研究结果表明，在低亲和力，弯曲的构象，整联蛋白胞外域往往围绕腿枢转;在中间构象，头部部分延伸，远离小腿。在完全开放的活动状态下，αIIbβ 3是柔性的，并且头片和小腿之间的运动伴随着跨膜螺旋的波动。在中尺度，弯曲的整合素只形成不稳定的粘连，但中间或开放构象稳定的粘连。这些研究揭示了一种机制，通过这种机制，在肌动蛋白逆行流动的存在下，配体结合亲和力的微小变化和配体结合寿命的增加稳定了αIIbβ 3整合素粘附。
The platelet integrin αIIbβ3undergoes long-range conformational transitions associated with its functional conversion from inactive (low-affinity) to active (high-affinity) during hemostasis. Although new conformations that are intermediate between the well-characterized bent and extended states have been identified, their molecular dynamic properties and functions in the assembly of adhesions remain largely unexplored. In this study, we evaluated the properties of intermediate conformations of integrin αIIbβ3and characterized their effects on the assembly of adhesions by combining all-atom simulations, principal component analysis, and mesoscale modeling. Our results show that in the low-affinity, bent conformation, the integrin ectodomain tends to pivot around the legs; in intermediate conformations, the headpiece becomes partially extended, away from the lower legs. In the fully open, active state, αIIbβ3is flexible, and the motions between headpiece and lower legs are accompanied by fluctuations of the transmembrane helices. At the mesoscale, bent integrins form only unstable adhesions, but intermediate or open conformations stabilize the adhesions. These studies reveal a mechanism by which small variations in ligand binding affinity and enhancement of the ligand-bound lifetime in the presence of actin retrograde flow stabilize αIIbβ3integrin adhesions.