Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera
Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera
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DOI：
10.1038/s41598-019-56177-5
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发表时间：
2019-12-23
影响因子：
4.6
通讯作者：
Kim, Jeong-Hoon
中科院分区：
文献类型：
--
作者：
Kim, Kidae;Lee, Dong Ho;Kim, Jeong-Hoon
蛋白质水解靶向嵌合体（PROTAC）是一种新兴的策略，通过诱导靶蛋白与E3遍在蛋白连接酶之间的接近来促进靶蛋白降解。尽管已经证明了PROTAC对许多蛋白质的成功降解，但尚未探索决定PROTAC靶向蛋白质降解性的因素。在这项研究中，我们开发了von Hippel-Lindau-Cereblon（VHL-CRBN）异二聚化PROTAC，诱导CRBN降解，但不诱导VHL降解。定量蛋白质组学分析进一步揭示VHL-CRBN异二聚化PROTAC诱导CRBN降解，但不诱导众所周知的免疫调节药物（IMiD）新底物IKAROS家族锌指1（IKZF 1）和-3（IZKF 3）降解。此外，CRBN和雄激素受体（AR）的无序区域的截短减弱了它们的PROTAC诱导的降解，并且无序区域与稳定的CRBN或AR的连接促进了PROTAC诱导的降解。因此，这些结果表明，目标蛋白质的内在无序区域是有效的蛋白质水解所必需的，提供了一个新的标准，选择可降解的蛋白质靶。
Proteolysis targeting chimeras (PROTACs) are an emerging strategy for promoting targeted protein degradation by inducing the proximity between targeted proteins and E3 ubiquitin ligases. Although successful degradation of numerous proteins by PROTACs has been demonstrated, the elements that determine the degradability of PROTAC-targeted proteins have not yet been explored. In this study, we developed von Hippel-Lindau-Cereblon (VHL-CRBN) heterodimerizing PROTACs that induce the degradation of CRBN, but not VHL. A quantitative proteomic analysis further revealed that VHL-CRBN heterodimerizing PROTACs induced the degradation of CRBN, but not the well-known immunomodulatory drug (IMiD) neo-substrates, IKAROS family zinc finger 1 (IKZF1) and -3 (IZKF3). Moreover, truncation of disordered regions of CRBN and the androgen receptor (AR) attenuated their PROTAC-induced degradation, and attachment of the disordered region to stable CRBN or AR facilitated PROTAC-induced degradation. Thus, these results suggest that the intrinsically disordered region of targeted proteins is essential for efficient proteolysis, providing a novel criterion for choosing degradable protein targets.