Multiple Cryptic Binding Sites are Necessary for Robust Fibronectin Assembly: An In Silico Study.
Multiple Cryptic Binding Sites are Necessary for Robust Fibronectin Assembly: An In Silico Study.
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DOI：
10.1038/s41598-017-18328-4
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发表时间：
2017-12-22
影响因子：
4.6
通讯作者：
Weinberg SH
中科院分区：
文献类型：
--
作者：
Lemmon CA;Weinberg SH
细胞外基质蛋白纤连蛋白（FN）组装成弹性的、不溶性原纤维的机制仍然知之甚少。FN原纤维形成需要细胞产生的力，其暴露隐藏在FN III型结构域中的隐蔽FN-FN结合位点。隐蔽结合位点的数量和位置一直存在争议，但实验证据表明，多个域可能含有FN-FN结合位点。需要依赖细胞的力量来产生FN原纤维限制了对组装机制的研究。为了解决这个问题，我们使用最近开发的生物物理模型的fibrillogenesis测试竞争的假设的位置和数量的隐蔽FN-FN结合位点，并量化这些分子的改变组装FN原纤维性能的影响。模拟预测，单个FN-FN结合位点促进可忽略的原纤维形成或产生既不稳健也不生理的FN原纤维。然而，包含多个FN-FN结合位点预测稳健的原纤维形成，其最低限度地依赖于单个结构域的性质。多个FN-FN结合位点模型预测了一个异质性原纤维人口，其中包含两种不同的表型，具有独特的粘弹性，我们推测这可能发挥了关键作用，在细胞外基质的发展和再生组织中产生异质性的机械信号。
The mechanism of assembly of the extracellular matrix protein fibronectin (FN) into elastic, insoluble fibrils is still poorly understood. FN fibrillogenesis requires cell-generated forces, which expose cryptic FN-FN binding sites buried in FN Type III domains. The number and location of cryptic binding sites have been debated, but experimental evidence suggests multiple domains may contain FN-FN binding sites. The requirement of cell-dependent forces to generate FN fibrils restricts investigation of the mechanism of assembly. To address this, we use a recently developed biophysical model of fibrillogenesis to test competing hypotheses for the location and number of cryptic FN-FN binding sites and quantify the effect of these molecular alterations on assembled FN fibril properties. Simulations predict that a single FN-FN binding site facilitates either negligible fibrillogenesis or produces FN fibrils that are neither robust nor physiological. However, inclusion of multiple FN-FN binding sites predicts robust fibrillogenesis, which minimally depends on individual domain properties. Multiple FN-FN binding site models predict a heterogeneous fibril population that contains two distinct phenotypes with unique viscoelastic properties, which we speculate may play a key role in generating heterogeneous mechanical signaling in the extracellular matrix of developing and regenerating tissues.
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影响因子：
3.4
作者：
Lemmon, Christopher A.;Chen, Christopher S.;Romer, Lewis H.
通讯作者：
Romer, Lewis H.
影响因子：
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通讯作者：
Hocking, DC
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通讯作者：
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