CRL4s: the CUL4-RING E3 ubiquitin ligases - PubMed (original) (raw)

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CRL4s: the CUL4-RING E3 ubiquitin ligases

Sarah Jackson et al. Trends Biochem Sci. 2009 Nov.

Abstract

The evolutionarily conserved cullin family proteins can assemble as many as 400 distinct E3 ubiquitin ligase complexes that regulate diverse cellular pathways. CUL4, one of three founding cullins conserved from yeast to humans, uses a large beta-propeller protein, DDB1, as a linker to interact with a subset of WD40 proteins that serve as substrate receptors, forming as many as 90 E3 complexes in mammals. Many CRL4 complexes are involved in chromatin regulation and are frequently hijacked by different viruses.

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Figures

Figure 1

Figure 1. Assembly of Cullin–RING ubiquitin ligases (CRLs)

The cullin-ROC family of E3 ligases regulates the ubiquitylation of many substrates by assembling into multiple distinct E3 ligases. Each cullin uses a modular assembly to recruit different substrates to a common catalytic core by varying its substrate receptor. Cullin family members (green) from different organisms share similar mechanisms for assembling a multi-subunit complex to ubiquitylate specific substrate protein (light blue). An N-terminal domain interacts either directly with a protein motif (orange) present in substrate receptors (black) or via a linker (blue). Separately, a C-terminal domain binds with a small RING protein (ROC1 or ROC2, yellow) which recruits and allosterically activates an E2 enzyme (red) that transfers ubiquitin (Ub; color) to the substrate. Cullins are activated by the covalent conjugation with a ubiquitin-like modifier, NEDD8 (Nd8; purple). Human cells express an estimated 78 F-box proteins, 205 BTB proteins, about 90 DWD proteins and an estimated 50 BC-box proteins.

Figure 2

Figure 2. Schematic comparison of CUL4 proteins and mouse Cul4A mutants

A. Human cells contain two CUL4 genes encoding CUL4A (NP_001008895) and two isoforms of CUL4B (NP_001073341 and NP_003579.3) proteins which differ by only 22 amino acids at the N-terminus. B. Wild type mouse Cul4A gene and comparison of three targeted Cul4A mutants. Filled and open boxes denote coding and non-coding exons, respectively. Exons encoding the DDB1 and ROC 1 binding regions in CUL4A have been noted. Three mouse models targeting Cul4A have been generated to date, deleting exon 1, exons 4-8, and exons 17-19, respectively. Discrepancies in reported phenotypes might be due to unintentional disruption of a nearby neighboring gene, Pcid2.

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