SODP调控SOCE进程的分子机制

Store-operated calcium entry (SOCE) is one of the basic processes in cell activities. During the activation of SOCE, calcium depletion from Endoplasmic Reticulum (ER) leads to the self-oligomerization of calcium sensor STIM1, and then activate the opening of calcium channel Orai1 on Plasma Membrane (PM)and calcium influx. However, the molecule mechanism of SOCE deactviation remains unknown. We have recently identified a protein molecule named SODP. This protein not only sensors intracellular calcium, but also is capable of binding and inhibiting the self-oligomerization of STIM1 molecule. It is a potential molecule which plays an important role in the closing of Orai1 channel. This application will take advantage of the combination of various techniques from biochemistry, cell biology and calcium imaging to search for the interaction module of STIM1 and SODP, determine the complex structure of STIM1/SODP, address the binding details between them, finally elucidate the molecule mechanism of SOCE regulation. Our results will be vital for the further understanding of SOCE, and also provide the basis of designing and screening small molecules to regulate SOCE, eventually shed the light on the treatment of immunodeficiency disease and neurodegenerative disease.

钙库操纵的钙离子内流（SOCE）是细胞生命活动中的基本进程。在SOCE的激活过程中，内质网钙池耗竭导致钙离子感受器STIM1分子自聚集并激活外膜钙离子通道Orai1引起钙离子内流。然而，钙库内钙离子重新填充后，SOCE失活的机制却一直不清楚。申请人最近鉴定出一个蛋白质分子（SODP），不仅可以感受钙离子，而且结合并抑制STIM1分子的自聚集，有可能发挥关闭Orai1的重要作用.本项目拟综合利用生物化学、细胞生物学和钙离子成像技术来寻找STIM1与SODP发生相互作用的具体片段，解析STIM1/SODP复合物结构，剖析两者结合的分子细节，最终阐明SODP调控SOCE失活的分子机制。本项目的研究结果对理解SOCE进程将会产生重要的影响，也为进一步设计并筛选小分子抑制剂调节SOCE提供分子基础，并最终为免疫缺陷和神经退行性疾病的治疗提供理论指导意义。

本研究围绕鉴定出的SODP蛋白在SOCE进程中的功能，以及SODP与STIM1及Orai1之间的相互作用展开一系列实验，发现SODP 能高效结合 STIM1 分子,竞争性地分开STIM1-Orai1 复合物，并在SOCE进程中扮演着关键的作用，能快速够阻止胞外钙离子的内流。