Elucidating the Membrane Insertion Mechanism of Chloride Intracellular Channel Proteins

Chloride Intracellular Channels (CLICs) are a family of 6 proteins that have in common a C-terminal CLIC module and chloride-selective ion channel activity. CLIC1 is a 241 amino-acid protein involved in the regulation of the cell cycle, in particular it is overexpressed in a number of cancer cells. However, to date little information exists as to its structure and the factors that influence its insertion into membranes. Here we propose to supplement previous neutron reflectivity experiments with data collected using a deuterated form of the CLIC-1 protein. This will be used in combination with a broad range of ongoing biophysical characterisation to establish the mechanism of CLIC1 chloride channel insertion as a function of membrane charge. This will be an initial step to understand how CLIC1 functions in tumour cells and will allow specific treatments to be designed to interrupt it.

氯化物细胞内通道（Chloride Intracellular Channels, CLICs）是一类包含6种蛋白质的家族，它们共同具有C端CLIC模块（CLIC module）及氯化物选择性离子通道活性。CLIC1是由241个氨基酸组成的蛋白质，参与细胞周期调控，尤其在多种癌细胞中存在过表达现象。然而，迄今为止，关于其结构及影响其插入膜的因素的信息仍十分有限。在此，我们提议利用氘代形式（deuterated form）的CLIC1蛋白收集的数据，补充先前开展的中子反射实验（neutron reflectivity experiments）。这些数据将与广泛进行的生物物理表征（biophysical characterisation）相结合，以确立CLIC1氯化物通道插入机制与膜电荷的依赖关系。这将是理解CLIC1在肿瘤细胞中功能的初步步骤，并将为设计针对性治疗方案以阻断其作用提供基础。