Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition
Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition
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DOI：
10.1016/j.cell.2011.06.025
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发表时间：
2011-08-05
期刊：
影响因子：
64.5
通讯作者：
Haucke, Volker
中科院分区：
文献类型：
--
作者：
von Kleist, Lisa;Stahlschmidt, Wiebke;Haucke, Volker
网格蛋白介导的内吞作用（CME）调节许多细胞生理过程，如生长因子和受体的内化，病原体的进入和突触传递。在内吞网络中，网格蛋白通过其末端结构域（TD）作为包被纹孔组装和解离的中心组织平台。我们报告的设计和合成的两种化合物命名的pitstops，选择性地阻止内吞配体协会与网格蛋白TD的X-射线晶体学证实。Pitstop诱导的网格蛋白TD功能抑制急性干扰受体介导的内吞作用、HIV进入和突触囊泡再循环。内吞抑制是由网格蛋白外壳组件，包括FCHo，网格蛋白，和发动蛋白的寿命急剧增加，表明网格蛋白TD调节包被的坑动态。Pitstops提供了新的工具来解决网格蛋白在细胞生理学中的功能，具有作为病毒和病原体进入的抑制剂以及作为细胞信号传导的调节剂的潜在应用。
Clathrin-mediated endocytosis (CME) regulates many cell physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. Within the endocytic network, clathrin functions as a central organizing platform for coated pit assembly and dissociation via its terminal domain (TD). We report the design and synthesis of two compounds named pitstops that selectively block endocytic ligand association with the clathrin TD as confirmed by X-ray crystallography. Pitstop-induced inhibition of clathrin TD function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling. Endocytosis inhibition is caused by a dramatic increase in the lifetimes of clathrin coat components, including FCHo, clathrin, and dynamin, suggesting that the clathrin TD regulates coated pit dynamics. Pitstops provide new tools to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry and as modulators of cell signaling.