Can a bulky glycocalyx promote catch bonding in early integrin adhesion? Perhaps a bit.
Can a bulky glycocalyx promote catch bonding in early integrin adhesion? Perhaps a bit.
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庞大的糖萼能否促进早期整合素粘附中的捕获结合？
DOI：
10.1101/2023.03.16.532909
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Blanchard,Aaron
中科院分区：
文献类型：
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作者：
Blanchard,Aaron
许多类型的癌细胞过度表达庞大的糖蛋白，形成厚厚的糖萼层。糖萼在物理上将细胞与其周围环境分开，但最近的研究表明，糖萼可以相反地增加对软组织的粘附，从而促进癌细胞的转移。发生这种令人惊讶的现象是因为糖萼迫使细胞表面上的粘附分子（称为整合素）形成簇。这些整合素簇具有协同效应，使它们能够与周围组织形成比同等数量的非簇化整合素更强的粘附力。近年来，这些合作机制受到了密切关注。对糖萼介导的粘附的生物物理基础有更细致的了解可以发现治疗靶点，加深我们对癌症转移的一般理解，并阐明远远超出癌症研究领域的一般生物物理过程。这项工作检验了这样的假设：糖萼具有增加聚集的整联蛋白所经历的机械张力的额外作用。整合素充当进行捕捉键合的机械传感器，这意味着相对于经历低张力的整合素的寿命，施加中等张力会增加整合素键的寿命。在这项工作中，整合素张力的三态化学机械捕捉键模型用于研究大糖萼存在下的捕捉键合。应用伪稳态近似，该近似依赖于这样的假设：整合素键动力学发生的时间尺度比质膜和基底之间完全粘附的演化快得多。力相关的动力学速率常数用于计算高斯形粘附几何形状的整合素-配体键的稳态分布。然后在存在和不存在卡扣粘合的情况下分析系统能量和粘合几何形状之间的关系，以评估卡扣粘合改变粘合形成的能量的程度。该模型表明，庞大的糖萼可以轻微触发捕获键合，从而将粘附边缘处的整合素的键合寿命延长高达 100%。对于某些粘附几何形状，粘附内整合素-配体键的总数预计将增加高达 ~ 60%。预计捕获键合会将粘附形成的活化能降低 ~ 1–4 kBT，这意味着粘附成核的动力学速率增加 ~ 3–50 × 。这项工作揭示了整合素机制和聚类可能都有助于糖萼介导的转移。图形摘要
Many types of cancer cells overexpress bulky glycoproteins to form a thick glycocalyx layer. The glycocalyx physically separates the cell from its surroundings, but recent work has shown that the glycocalyx can paradoxically increase adhesion to soft tissues and therefore promote the metastasis of cancer cells. This surprising phenomenon occurs because the glycocalyx forces adhesion molecules (called integrins) on the cell’s surface into clusters. These integrin clusters have cooperative effects that allow them to form stronger adhesions to surrounding tissues than would be possible with equivalent numbers of un-clustered integrins. These cooperative mechanisms have been intensely scrutinized in recent years. A more nuanced understanding of the biophysical underpinnings of glycocalyx-mediated adhesion could uncover therapeutic targets, deepen our general understanding of cancer metastasis, and elucidate general biophysical processes that extend far beyond the realm of cancer research. This work examines the hypothesis that the glycocalyx has the additional effect of increasing mechanical tension experienced by clustered integrins. Integrins function as mechanosensors that undergo catch bonding—meaning the application of moderate tension increases integrin bond lifetime relative to the lifetime of integrins experiencing low tension. In this work, a three-state chemomechanical catch bond model of integrin tension is used to investigate catch bonding in the presence of a bulky glycocalyx. A pseudo-steady-state approximation is applied, which relies on the assumption that integrin bond dynamics occur on a much faster timescale than the evolution of the full adhesion between the plasma membrane and the substrate. Force-dependent kinetic rate constants are used to calculate a steady-state distribution of integrin-ligand bonds for Gaussian-shaped adhesion geometries. The relationship between the energy of the system and adhesion geometry is then analyzed in the presence and absence of catch bonding in order to evaluate the extent to which catch bonding alters the energetics of adhesion formation. This modeling suggests that a bulky glycocalyx can lightly trigger catch bonding, increasing the bond lifetime of integrins at adhesion edges by up to 100%. The total number of integrin-ligand bonds within an adhesion is predicted to increase by up to ~ 60% for certain adhesion geometries. Catch bonding is predicted to decrease the activation energy of adhesion formation by ~ 1–4 kBT, which translates to a ~ 3–50 × increase in the kinetic rate of adhesion nucleation. This work reveals that integrin mechanics and clustering likely both contribute to glycocalyx-mediated metastasis.Graphical abstract