2. Academic Validation
  3. CAND1 and CAND2 drive CUL4 substrate receptor exchange with largely comparable biochemical efficiency, unlike their relative effects on CUL1

CAND1 and CAND2 drive CUL4 substrate receptor exchange with largely comparable biochemical efficiency, unlike their relative effects on CUL1

  • Structure. 2026 Mar 20:S0969-2126(26)00056-0. doi: 10.1016/j.str.2026.02.015.
Kankan Wang 1,  Sebastian Kenny 2,  Zhana Chagan 1,  Lihong Li 1,  Chittaranjan Das 2,  Xing Liu 3
Affiliations

Affiliations

  • 1 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
  • 2 Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
  • 3 Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA. Electronic address: [email protected].
PMID: 41864201 DOI: 10.1016/j.str.2026.02.015
Abstract

Cullin-RING ubiquitin ligases (CRLs) regulate diverse cellular processes by dynamically recruiting substrate receptors onto conserved cullin-RING scaffolds. CAND1 and CAND2 function as substrate receptor exchange factors for CRL1, but CAND2 displays reduced efficiency in CRL1 disassembly, exhibits tissue-specific expression, and shows distinct disease associations, raising questions about its function in Other CRL subfamilies. Here, we define the regulatory roles of CAND1 and CAND2 in CRL4 remodeling. Using genetic perturbation, real-time kinetic analyses, and quantitative interaction proteomics, we show that both CAND proteins promote CRL4-mediated protein degradation and enhance the dynamic exchange of DDB1·DCAF substrate receptor modules, likely through conserved yet distinct structural features. In contrast to their differential efficiencies in CRL1 disassembly, CAND1 and CAND2 exhibit similar kinetic parameters and comparable exchange efficiencies across most of the CRL4 complexes. These findings establish CAND1 and CAND2 as bona fide CRL4 exchange factors and reveal biochemical distinctions between CRL4 and CRL1 regulation.

Keywords

CAND2; Cullin-RING ubiquitin ligases; dynamics of protein complexes; protein exchange factor.

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