9pvh
Human Cullin-4 in complex with CAND2
Structural highlights
FunctionCUL4A_HUMAN Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. In association with RBX1, DDB1 and DDB2 is required for histone H3 and histone H4 ubiquitination in response to ultraviolet and may be important for subsequent DNA repair. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedCullin-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. CAND1 and CAND2 drive CUL4 substrate receptor exchange with largely comparable biochemical efficiency, unlike their relative effects on CUL1.,Wang K, Kenny S, Chagan Z, Li L, Das C, Liu X Structure. 2026 Jun 4;34(6):963-976.e6. doi: 10.1016/j.str.2026.02.015. Epub 2026 , Mar 20. PMID:41864201[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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