Chemical Inhibitors of Protein Translocation

蛋白质易位的化学抑制剂

• 批准号: 7734850
• 负责人: Ramanujan S Hegde
• 金额: $ 12.24万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734850
• 关键词: Anabolism; Cells; Chemicals; Complex; Cultured Cells; Endoplasmic Reticulum; Event; Goals; In Vitro; Individual; Life; Membrane Proteins; Methods; Peptide Signal Sequences; Pharmaceutical Preparations; Physiology; Process; Protein translocation; Proteins; Resistance; Role; Secretory Cell; Signal Transduction; Specificity; Stress; Substrate Specificity; Testing; Toxic effect; base; in vivo; inhibitor/antagonist; interest; novel; protein aggregation; protein degradation; response; small molecule; tool

To develop new methods and probes for protein translocation, we have been developing pharmacologic methods of modulating this process in vivo. We have recently synthesized and characterized a novel small molecule inhibitor of cotranslational protein translocation. This compound (called cotransin) was demonstrated both in vitro and in cultured cells to inihibit the translocation of some, but not other proteins. Remarkably, this substrate-specificity was found to be encoded in the signal sequence. Thus, the sensitivity or resistance to cotransin can be conferred to any protein of interest simply by the choice of signal. The target of cotransin has been identified, and appears to be the Sec61 complex, the central component of the protein translocation channel. These tools and findings now open the way to selectively and potently modulate the translocation of individual substrates in live cells. This approach is now being applied to study the role of protein translocation in various cellular events such a protein aggregation and toxicity, protein degradation, and the cellular response to ER stress. In addition, analogoues of cotransin are now being tested for their effects on a variety of substrates to determine whether specificity of inhibition can be modulated. And finally, cotransin is being used as a tool to dissect the mechanistic basis of signal sequence interaction with the translocon, a decisive step in protein translocation.

为了开发蛋白质易位的新方法和探针，我们一直在开发在体内调节该过程的药理方法。我们最近综合并表征了一种新型的小分子抑制剂的共晶蛋白易位。在体外和培养细胞中都证明了这种化合物（称为二兰氏素），以毫利某些但没有其他蛋白质的易位。值得注意的是，发现该基材特异性在信号序列中编码。因此，仅通过选择信号，就可以赋予对任何感兴趣的蛋白质的敏感性或抗性。已经鉴定出二兰氏素的靶标，并且似乎是SEC61复合物，这是蛋白质易位通道的中心分量。这些工具和发现现在开辟了道路，以选择性地调节活细胞中各个基板的易位。现在，正在应用这种方法来研究蛋白质易位在各种细胞事件中的作用，例如蛋白质聚集和毒性，蛋白质降解以及对ER应激的细胞反应。此外，现在正在对二兰氏素的类似物对各种底物的影响进行测试，以确定是否可以调节抑制的特异性。最后，二兰氏素被用作剖析信号序列相互作用与转运的机械基础的工具，这是蛋白质易位的决定性步骤。