CUL4A
Description
The CUL4A (cullin 4A) is a protein-coding gene located on chromosome 13.
CUL4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.
CUL4A protein is 759 amino acids long and forms an extended, rigid structure primarily consisting of alpha-helices. At the N-terminus, CUL4A binds to the beta-propeller of the DDB1 adaptor protein which interacts with numerous DDB1-CUL4-Associated Factors (DCAFs). As a result, the N-terminus is crucial for the recruitment of substrates for the ubiquitin ligase complex. At the C-terminal end, CUL4A interacts with the RBX1/ROC1 protein via its RING domain. RBX1 is a core component of Cullin-RING ubiquitin ligase (CRL) complexes and functions to recruit E2 ubiquitin conjugating enzymes. Therefore, the C-terminus of CUL4A - along with RBX1 and activated E2 enzymes - compose the catalytic core of CRL4 complexes.
CUL4A is a core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes that mediate the ubiquitination of target proteins. It acts as a scaffold protein, contributing to catalysis by positioning 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. CUL4A directs the ubiquitination of various target proteins, including JUN via DCX(DET1-COP1), XPC via DCX(DDB2), histones H3-H4 via DCX(DDB2), CDT1 and p53/TP53 via DCX(DTL), and CRY1 via the DDB1-CUL4A-DTL E3 ligase complex. It also plays a role in the ubiquitination of CDKN1B/p27kip in association with DDB1 and SKP2 and HOXA9. CUL4A is part of the DesCEND pathway, containing either TRPC4AP or DCAF12 as substrate-recognition component, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The DCX(AMBRA1) complex acts as a master regulator of the transition from G1 to S cell phase by mediating the ubiquitination of phosphorylated cyclin-D (CCND1, CCND2, and CCND3). It also regulates Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating the ubiquitination and degradation of the Elongin-C (ELOC) component of CRL5 complexes. In collaboration with CUL4B, CUL4A contributes to ribosome biogenesis. It can self-associate and is a component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes, including the CSA complex (DCX(ERCC8) complex), the DCX(DET1-COP1) complex, the DCX(DDB2) complex, the DCX(DTL) complex, and the DCX(AMBRA1) complex.
CUL4A is also known as -.
