Mechanobiology predicts raft formations triggered by ligand-receptor activity across the cell membrane
Mechanobiology predicts raft formations triggered by ligand-receptor activity across the cell membrane
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DOI：
10.1016/j.jmps.2020.103974
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发表时间：
2020-08-01
影响因子：
5.3
通讯作者：
Fraldi, Massimiliano
中科院分区：
文献类型：
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作者：
Carotenuto, Angelo R.;Lunghi, Laura;Fraldi, Massimiliano
不同类型的配体结合受体聚集在增厚的细胞膜上，即脂筏，是一种实验观察到的现象。尽管其对细胞反应的影响已被深入研究，但在配体结合过程中，涉及活性受体和周围脂质膜的机械过程和多物理场之间的耦合作用尚未被理解。具体来说，这项工作的重点是g蛋白偶联受体（gpcr），这是动物中最广泛的跨膜蛋白群，通过化学信号通路调节特定的细胞过程，涉及细胞内环境中由活性gpcr产生的环腺苷单磷酸（cAMP）及其外排之间的协同平衡，由多药耐药蛋白（MRPs）转运体介导。本文基于活性gpcr和MRPs的能量学、多尺度几何变化和质量平衡之间的相互作用，开发了一种多物理场方法，包括扩散和结合与解结合动力学。由于获得的能量既依赖于运动学，也依赖于物种密度的变化，所以质量平衡和线性动量的平衡是耦合的，并且控制着细胞膜的时空演化。涉及细胞膜脂质排序的重塑和改变的机械生物学允许预测转运体和活性受体的动力学-与实验观察到的cAMP水平完全一致-以及后者如何触发筏形成和聚集在这些位置。在目前关于严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的科学辩论中，基于脂筏经常作为病毒入境的确定事实，人们认为，考虑机械生物学方面之间强耦合的方法甚至可能有助于更好地理解膜介导的现象，如COVID-19病毒-细胞相互作用。(C) 2020 Elsevier Ltd.版权所有。
Clustering of ligand-binding receptors of different types on thickened isles of the cell membrane, namely lipid rafts, is an experimentally observed phenomenon. Although its influence on cell's response is deeply investigated, the role of the coupling between mechanical processes and multiphysics involving the active receptors and the surrounding lipid membrane during ligand-binding has not yet been understood. Specifically, the focus of this work is on G-protein-coupled receptors (GPCRs), the widest group of transmembrane proteins in animals, which regulate specific cell processes through chemical signalling pathways involving a synergistic balance between the cyclic Adenosine Monophosphate (cAMP) produced by active GPCRs in the intracellular environment and its efflux, mediated by the Multidrug Resistance Proteins (MRPs) transporters. This paper develops a multiphysics approach based on the interplay among energetics, multiscale geometrical changes and mass balance of species, i.e. active GPCRs and MRPs, including diffusion and kinetics of binding and unbinding. Because the obtained energy depends upon both the kinematics and the changes of species densities, balance of mass and of linear momentum are coupled and govern the space-time evolution of the cell membrane. The mechanobiology involving remodelling and change of lipid ordering of the cell membrane allows to predict dynamics of transporters and active receptors -in full agreement with experimentally observed cAMP levels- and how the latter trigger rafts formation and cluster on such sites. Within the current scientific debate on Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) and on the basis of the ascertained fact that lipid rafts often serve as an entry port for viruses, it is felt that approaches accounting for strong coupling among mechanobiological aspects could even turn helpful in better understanding membrane-mediated phenomena such as COVID-19 virus-cell interaction. (C) 2020 Elsevier Ltd. All rights reserved.