Center for Biophysics & Department of Theoretical Physics, Saarland University, Saarbrücken 66041, Germany; Department of Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg 66421, Germany; Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg 66421, Germany.
Department of Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg 66421, Germany.
J Theor Biol. 2019 Jun 7;470:64-75. doi: 10.1016/j.jtbi.2019.02.010. Epub 2019 Mar 7.
Release of Ca from endoplasmatic retriculum (ER) Ca stores causes stromal interaction molecules (STIM) in the ER membrane and ORAI proteins in the plasma membrane (PM) to interact and form the Ca release activated Ca (CRAC) channels, which represent a major Ca entry route in non-excitable cells and thus control various cell functions. It is experimentally possible to mutate ORAI1 proteins and therefore modify, especially block, the Ca influx into the cell. On the basis of the model of Hoover and Lewis (2011), we formulate a reaction-diffusion model to quantify the STIM1-ORAI1 interaction during CRAC channel formation and analyze different ORAI1 channel stoichiometries and different ratios of STIM1 and ORAI1 in comparison with experimental data. We incorporate the inhibition of ORAI1 channels by ROS into our model and calculate its contribution to the CRAC channel amplitude. We observe a large decrease of the CRAC channel amplitude evoked by mutations of ORAI1 proteins.
内质网 (ER) 钙库中的钙释放会导致 ER 膜中的基质相互作用分子 (STIM) 和质膜 (PM) 中的 ORAI 蛋白相互作用并形成钙释放激活钙 (CRAC) 通道，这是非兴奋性细胞中主要的钙进入途径，从而控制各种细胞功能。实验上可以突变 ORAI1 蛋白，从而修饰，特别是阻断，细胞内的钙内流。基于 Hoover 和 Lewis（2011）的模型，我们制定了一个反应扩散模型来量化 CRAC 通道形成过程中的 STIM1-ORAI1 相互作用，并分析了不同的 ORAI1 通道化学计量和 STIM1 与 ORAI1 的不同比例与实验数据进行比较。我们将 ROS 对 ORAI1 通道的抑制作用纳入我们的模型，并计算其对 CRAC 通道振幅的贡献。我们观察到 ORAI1 蛋白突变引起的 CRAC 通道振幅的大幅下降。
