近日，美国哈佛大学刘如谦等研究人员合作实现，通过选择性分子胶水调节的紧凑型蛋白质降解标签的持续演化。该研究于2024年3月15日发表于国际一流学术期刊《科学》。

研究人员表示，条件性蛋白质降解标签（degron）通常长度大于100个氨基酸，或者由小分子触发，具有很大的脱靶效应，因此无法用作内源蛋白质水平的特异性调节剂。

研究人员开发了一种噬菌体辅助的分子胶水化合物持续演化平台（MG-PACE），并演化出一种36氨基酸锌指（ZF）degron（SD40），它能结合泛素连接酶底物受体cereblon与PT-179（一种正交沙利度胺衍生物）的复合体。

利用先导编辑技术在SD40框架内标记的内源性蛋白质会被惰性PT-179降解。SD40与配体结合的cereblon复合物的冷冻电镜结构，揭示了SD40活性和特异性的分子基础。这些努力建立了一个分子胶水化合物持续演化的系统，并提供了ZF标签，克服了现有degron的缺陷。

附：英文原文

Title: Continuous evolution of compact protein degradation tags regulated by selective molecular glues

Author: Jaron A. M. Mercer, Stephan J. DeCarlo, Shourya S. Roy Burman, Vedagopuram Sreekanth, Andrew T. Nelson, Moritz Hunkeler, Peter J. Chen, Katherine A. Donovan, Praveen Kokkonda, Praveen K. Tiwari, Veronika M. Shoba, Arghya Deb, Amit Choudhary, Eric S. Fischer, David R. Liu

Issue&Volume: 2024-03-15

Abstract: Conditional protein degradation tags (degrons) are usually >100 amino acids long or are triggered by small molecules with substantial off-target effects, thwarting their use as specific modulators of endogenous protein levels. We developed a phage-assisted continuous evolution platform for molecular glue complexes (MG-PACE) and evolved a 36–amino acid zinc finger (ZF) degron (SD40) that binds the ubiquitin ligase substrate receptor cereblon in complex with PT-179, an orthogonal thalidomide derivative. Endogenous proteins tagged in-frame with SD40 using prime editing are degraded by otherwise inert PT-179. Cryo–electron microscopy structures of SD40 in complex with ligand-bound cereblon revealed mechanistic insights into the molecular basis of SD40’s activity and specificity. Our efforts establish a system for continuous evolution of molecular glue complexes and provide ZF tags that overcome shortcomings associated with existing degrons.

DOI: adk4422

Source: https://www.science.org/doi/10.1126/science.adk4422