iTAG是一种经过优化的免疫调节药物（IMiD）诱导的降解子，用于在人和小鼠细胞中进行靶向蛋白质降解。
iTAG an optimized IMiD-induced degron for targeted protein degradation in human and murine cells.
作者信息
Bouguenina Habib, Nicolaou Stephanos, Le Bihan Yann-Vaï, Bowling Elizabeth A, Calderon Cheyenne, Caldwell John J, Harrington Brinley, Hayes Angela, McAndrew P Craig, Mitsopoulos Costas, Sialana Fernando Jr, Scarpino Andrea, Stubbs Mark, Thapaliya Arjun, Tyagi Siddhartha, Wang Hannah Z, Wood Francesca, Burke Rosemary, Raynaud Florence, Choudhary Jyoti, van Montfort Rob L M, Sadok Amine, Westbrook Thomas F, Collins Ian, Chopra Rajesh
机构信息
Centre for Cancer Drug Discovery, the Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.
Therapeutic Innovation Centre (THINC), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
出版信息
iScience. 2023 Jun 7;26(7):107059. doi: 10.1016/j.isci.2023.107059. eCollection 2023 Jul 21.
To address the limitation associated with degron based systems, we have developed iTAG, a synthetic tag based on IMiDs/CELMoDs mechanism of action that improves and addresses the limitations of both PROTAC and previous IMiDs/CeLMoDs based tags. Using structural and sequence analysis, we systematically explored native and chimeric degron containing domains (DCDs) and evaluated their ability to induce degradation. We identified the optimal chimeric iTAG(DCD23 60aa) that elicits robust degradation of targets across cell types and subcellular localizations without exhibiting the well documented "hook effect" of PROTAC-based systems. We showed that iTAG can also induce target degradation by murine CRBN and enabled the exploration of natural neo-substrates that can be degraded by murine CRBN. Hence, the iTAG system constitutes a versatile tool to degrade targets across the human and murine proteome.
为了解决基于降解子系统的局限性，我们开发了iTAG，这是一种基于免疫调节药物/ cereblon调节剂（IMiDs/CELMoDs）作用机制的合成标签，它改进并解决了PROTAC和先前基于IMiDs/CELMoDs的标签的局限性。通过结构和序列分析，我们系统地探索了含有天然和嵌合降解子的结构域（DCDs），并评估了它们诱导降解的能力。我们鉴定出了最佳的嵌合iTAG（DCD23 60aa），它能在不同细胞类型和亚细胞定位中引发靶标的强烈降解，而不会表现出基于PROTAC系统的“钩效应”。我们表明，iTAG还可以通过小鼠CRBN诱导靶标降解，并能够探索可被小鼠CRBN降解的天然新底物。因此，iTAG系统构成了一种通用工具，可用于降解人类和小鼠蛋白质组中的靶标。
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