小柯机器人

美国哈佛大学Christina M. Woo研究小组发现，E3连接酶适配子cereblon靶向C-末端的环状酰亚胺degron。2022年10月19日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示，泛素E3连接酶底物适配子cereblon（CRBN）是沙利度胺和来那度胺的靶标，这些治疗剂被用于治疗造血系统恶性肿瘤，并作为靶向蛋白降解的配体。这些药物被建议模仿自然发生的degron，然而，CRBN的沙利度胺结合结构域所识别的结构模体仍然是未知的。

研究人员发现，C端环状酰亚胺是翻译后的修饰，产生于谷氨酰胺或天冬酰胺残基的分子内环化，是CRBN底物上的生理性脱氮剂。当嵌入双功能化学降解剂中时，带有C端环状酰亚胺degron的二肽可替代沙利度胺。在体外和细胞中，在蛋白质的C端加入去离子会诱导CRBN依赖性泛素化和降解。在整个人类蛋白质组中，C端环状酰亚胺在生理上相关的时间范围内偶然形成，从而提供一个被CRBN内源性识别和去除的degron。C-末端环状酰亚胺degron的发现确定了一个可能影响CRBN的生理功能和治疗作用的调节过程。

附：英文原文

Title: The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron

Author: Ichikawa, Saki, Flaxman, Hope A., Xu, Wenqing, Vallavoju, Nandini, Lloyd, Hannah C., Wang, Binyou, Shen, Dacheng, Pratt, Matthew R., Woo, Christina M.

Issue&Volume: 2022-10-19

Abstract: The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide1, therapeutic agents used in the treatment of haematopoietic malignancies2,3,4 and as ligands for targeted protein degradation5,6,7. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to the C terminus of proteins induces CRBN-dependent ubiquitination and degradation in vitro and in cells. C-terminal cyclic imides form adventitiously on physiologically relevant timescales throughout the human proteome to afford a degron that is endogenously recognized and removed by CRBN. The discovery of the C-terminal cyclic imide degron defines a regulatory process that may affect the physiological function and therapeutic engagement of CRBN.

DOI: 10.1038/s41586-022-05333-5

Source: https://www.nature.com/articles/s41586-022-05333-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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