Tuning the mechanical stability of fibronectin type III modules through sequence variations
Tuning the mechanical stability of fibronectin type III modules through sequence variations
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DOI：
10.1016/j.str.2003.11.024
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发表时间：
2004-01-01
期刊：
影响因子：
5.7
通讯作者：
Vogel, V
中科院分区：
文献类型：
--
作者：
Craig, D;Gao, M;Vogel, V
细胞可以通过在施加机械力的同时拉伸细胞外基质蛋白来切换它们的功能状态。使用转向分子动力学，我们研究了如何从细胞粘附蛋白纤连蛋白的FnIII模块的机械稳定性是由其氨基酸序列的自然变异的影响。尽管非常相似的三级结构，FnIII模块共享低序列同源性。相反，跨多个物种的相同FnIII模块的序列同源性显著更高，表明序列变异性在功能上是显著的。我们的研究发现，FnIII模块的机械稳定性可以通过仅几个关键氨基酸的取代来调整，通过改变水分子对在解折叠途径中早期断裂的氢键的访问。此外，机械解折叠的FnIII层级可以通过环境条件改变，例如FnIII的pH（10），或者通过与其他分子形成复合物，例如肝素与FnIII的结合（13）。
Cells can switch the functional states of extracellular matrix proteins by stretching them while exerting mechanical force. Using steered molecular dynamics, we investigated how the mechanical stability of FnIII modules from the cell adhesion protein fibronectin is affected by natural variations in their amino acid sequences. Despite remarkably similar tertiary structures, FnIII modules share low sequence homology. Conversely, the sequence homology for the same FnIII module across multiple species is notably higher, suggesting that sequence variability is functionally significant. Our studies find that the mechanical stability of FnIII modules can be tuned through substitutions of just a few key amino acids by altering access of water molecules to hydrogen bonds that break early in the unfolding pathway. Furthermore, the FnIII hierarchy of mechanical unfolding can be changed by environmental conditions, such as pH for FnIII(10), or by forming complexes with other molecules, such as heparin binding to FnIII(13).