Force-dependent isomerization kinetics of a highly conserved proline switch modulates the mechanosensing region of filamin
Force-dependent isomerization kinetics of a highly conserved proline switch modulates the mechanosensing region of filamin
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DOI：
10.1073/pnas.1319448111
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发表时间：
2014-04-15
影响因子：
11.1
通讯作者：
Rief, Matthias
中科院分区：
文献类型：
--
作者：
Rognoni, Lorenz;Moest, Tobias;Rief, Matthias
由顺反异构化控制的脯氨酸开关在广泛的生物过程中已成为一种特别有效的调节机制。在这项研究中，我们使用单分子力学测量来建立一个完整的动力学和能量描述，描述在人细丝蛋白的力敏感区域20中高度保守的Pro开关，以及Pro异构化是如何调节力敏感机制的。脯氨酸异构化在两种构象之间切换结构域20。稳定的顺式构象缓慢展开，有利于细丝素力敏结构域对20-21的自抑制闭合构象，反式构象促进的不稳定的无抑制构象。这些数据提供了支持这种二元开关功能的折叠机制的详细见解，并阐明了它在调制力感觉方面的非凡效率，从而将两个以前没有连接的调节机制--脯氨酸开关和机械感觉--结合在一起。
Proline switches, controlled by cis-trans isomerization, have emerged as a particularly effective regulatory mechanism in a wide range of biological processes. In this study, we use single-molecule mechanical measurements to develop a full kinetic and energetic description of a highly conserved proline switch in the force-sensing domain 20 of human filamin and how prolyl isomerization modulates the force-sensing mechanism. Proline isomerization toggles domain 20 between two conformations. A stable cis conformation with slow unfolding, favoring the autoinhibited closed conformation of filamin's force-sensing domain pair 20-21, and a less stable, uninhibited conformation promoted by the trans form. The data provide detailed insight into the folding mechanisms that underpin the functionality of this binary switch and elucidate its remarkable efficiency in modulating force-sensing, thus combining two previously unconnected regulatory mechanisms, proline switches and mechanosensing.