2. Academic Validation
  3. CAND1 inhibits Cullin-2-RING ubiquitin ligases for enhanced substrate specificity

CAND1 inhibits Cullin-2-RING ubiquitin ligases for enhanced substrate specificity

  • Nat Struct Mol Biol. 2024 Jan 4. doi: 10.1038/s41594-023-01167-5.
Kankan Wang 1,  Stephanie Diaz 1 2,  Lihong Li 1 3,  Jeremy R Lohman 1 4,  Xing Liu 5 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
  • 2 Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
  • 3 Center for Plant Biology, Purdue University, West Lafayette, IN, USA.
  • 4 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
  • 5 Department of Biochemistry, Purdue University, West Lafayette, IN, USA. [email protected].
  • 6 Center for Plant Biology, Purdue University, West Lafayette, IN, USA. [email protected].
PMID: 38177676 DOI: 10.1038/s41594-023-01167-5
Abstract

Through targeting essential cellular regulators for ubiquitination and serving as a major platform for discovering proteolysis-targeting chimera (PROTAC) drugs, Cullin-2 (CUL2)-RING ubiquitin ligases (CRL2s) comprise an important family of CRLs. The founding members of CRLs, the CUL1-based CRL1s, are known to be activated by CAND1, which exchanges the variable substrate receptors associated with the common CUL1 core and promotes the dynamic assembly of CRL1s. Here we find that CAND1 inhibits CRL2-mediated protein degradation in human cells. This effect arises due to altered binding kinetics, involving CAND1 and CRL2VHL, as we illustrate that CAND1 dramatically increases the dissociation rate of CRL2s but barely accelerates the assembly of stable CRL2s. Using PROTACs that differently recruit neo-substrates to CRL2VHL, we demonstrate that the inhibitory effect of CAND1 helps distinguish target proteins with different affinities for CRL2s, presenting a mechanism for selective protein degradation with proper pacing in the changing cellular environment.

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