On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation
On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation
复制标题
跨膜结构域对整合素激活亚基特异性敏感性的贡献作用
作者：
Giulia Pagani;H. Gohlke
整合素是α/β异二聚体跨膜粘附受体。有证据表明，它们的跨膜结构域（TMD）在激活后分离。据报道，整合素的激活敏感性存在亚单位特异性差异。然而，TMD的序列变化是否导致不同的TMD关联仍然是难以捉摸的。本文通过分子动力学模拟和结合自由能计算表明，整合素αIIbβ3、αvβ3和α5β1的TMD结合最为稳定；这种差异与tmd之间的交互差异有关。TMD结合稳定性的顺序与这些整合素的基础活性是平行的，这表明TMD的差异对整合素的构象自由能有决定性的影响。我们还确定了TMD解离时扣环解体的特定顺序，这表明整合素的闭合状态可能包括几个微观状态。我们的结果为TMD对整合素激活的亚单位特异性敏感性的可能贡献作用提供了前所未有的见解。
Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential TMD association has remained elusive. Here, we show by molecular dynamics simulations and association free energy calculations on TMDs of integrin αIIbβ3, αvβ3, and α5β1 that αIIbβ3 TMD is most stably associated; this difference is related to interaction differences across the TMDs. The order of TMD association stability is paralleled by the basal activity of these integrins, which suggests that TMD differences can have a decisive effect on integrin conformational free energies. We also identified a specific order of clasp disintegration upon TMD dissociation, which suggests that the closed state of integrins may comprise several microstates. Our results provide unprecedented insights into a possibly contributing role of TMD towards subunit-specific sensitivity of integrin activation.
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DOI：
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