2. Academic Validation
  3. 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

  • Sci Rep. 2019 Dec 23;9(1):19654. doi: 10.1038/s41598-019-56177-5.
Kidae Kim 1 2,  Dong Ho Lee 3,  Sungryul Park 1 2,  Seung-Hyun Jo 1 4,  Bonsu Ku 1,  Sung Goo Park 1 4,  Byoung Chul Park 1 2,  Yeong Uk Jeon 3,  Sunjoo Ahn 3 5,  Chung Hyo Kang 6 7,  Daehee Hwang 8,  Sehyun Chae 9,  Jae Du Ha 3,  Sunhong Kim 10 11,  Jong Yeon Hwang 12 13,  Jeong-Hoon Kim 14 15
Affiliations

Affiliations

  • 1 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
  • 2 Department of Proteome Structural biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 3 Therapeutics & Biotechnology, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 4 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 5 Department of Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 6 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 7 College of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 8 Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  • 9 Korea Brain Bank, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
  • 10 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea. [email protected].
  • 11 Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. [email protected].
  • 12 Therapeutics & Biotechnology, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. [email protected].
  • 13 Department of Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. [email protected].
  • 14 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea. [email protected].
  • 15 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. [email protected].
PMID: 31873151 DOI: 10.1038/s41598-019-56177-5
Abstract

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.

Figures
Products