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| Aliases | CRBN , MRT2, MRT2A, Cereblon | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 609262; MGI: 1913277; HomoloGene: 9461; GeneCards: CRBN; OMA:CRBN - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Cereblon is a protein that in humans is encoded by the CRBN gene. [5] The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN orthologs are highly conserved from plants to humans. [5]
Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). [6] This complex ubiquitinates a number of other proteins and marks them for degradation via the proteasome. Through a mechanism which has not been completely elucidated, this ubiquitination results in reduced levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. [7]
In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein. Furthermore, cereblon and DDB2 bind to DDB1 in a competitive manner. [7]
Cereblon binds to the large-conductance calcium-activated potassium channel (KCNMA1) and regulates its activity. [8] [9] Moreover, mice lacking this channel develop neurological disorders. [10]
The drug thalidomide binds to cereblon and changes which substrates can be degraded by it, which leads to an antiproliferative effect on myeloma cells and possibly the teratogenic effect on fetal development. [7] [11] [12] [13] Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects. [14] It is estimated that 10,000 to 20,000 children were affected. [15] However, the idea that cereblon modulation is responsible for the teratogenic activity of thalidomide in the chick and zebrafish was cast into doubt due to a 2013 report that pomalidomide (a more potent thalidomide analogue) does not cause teratogenic effects in these same model systems even though it binds with cereblon more strongly than thalidomide. [16] [17]
Mutations in the CRBN gene are associated with autosomal recessive nonsyndromic intellectual disability, [5] possibly as a result of dysregulation of calcium-activated potassium channels in the brain (see below) during development. [7]
Based on the finding that thalidomide and related analogues bind CRBN, heterobifunctional molecules were designed linking thalidomide to ligands for other proteins of interest. [18] [19] These molecules, termed proteolysis targeting chimeras (PROTACs) or protein degraders, recruit CRBN to a protein of interest, leading to its ubiquitination and subsequent degradation. This technology is being explored in clinical trials by a number of biotechnology companies such as Arvinas, C4 Therapeutics, and Kymera Therapeutics. [20]
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.
E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.
NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.
Cullin-4A 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.
DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene.
DNA damage-binding protein 1 is a protein that in humans is encoded by the DDB1 gene.
Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.
E3 ubiquitin-protein ligase SMURF2 is an enzyme that in humans is encoded by the SMURF2 gene which is located at chromosome 17q23.3-q24.1.
Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.
The human gene UBR1 encodes the enzyme ubiquitin-protein ligase E3 component n-recognin 1.
Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene. Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.
Denticleless protein homolog is a protein that in humans is encoded by the DTL gene.
Ubiquitin-like modifier-activating enzyme 7 is a protein that in humans is encoded by the UBA7 gene.
Protein VPRBP is a protein that in humans is encoded by the VPRBP gene.
Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form Cullin-RING ubiquitin ligases (CRLs) that are highly diverse and play a role in myriad cellular processes, most notably protein degradation by ubiquitination.
DDB1 and CUL4 associated factor 17 is a protein that in humans is encoded buy the DCAF17 gene.
Cereblon E3 ligase modulators, also known as immunomodulatory imide drugs (IMiDs), are a class of immunomodulatory drugs containing an imide group. The IMiD class includes thalidomide and its analogues. These drugs may also be referred to as 'Cereblon modulators'. Cereblon (CRBN) is the protein targeted by this class of drugs.
DDB1 and CUL4 associated factor 15 is a protein that in humans is encoded by the DCAF15 gene.
Molecular glue refers to a class of chemical compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems. These molecules act as "glue" by enhancing the affinity between proteins, ultimately influencing various cellular processes. Molecular glue compounds have gained significant attention in the fields of drug discovery, chemical biology, and fundamental research due to their potential to modulate protein interactions, and thus, impact various cellular pathways. They have unlocked avenues in medicine previously thought to be "undruggable".
Nicolas H. Thomä is a German researcher, full professor at the EPFL School of Life Sciences and Director of the Paternot Chair for Cancer Research in Lausanne, Switzerland. He is a biochemist and structural biologist and a leading researcher in the fields of ubiquitin ligase biology and DNA repair.
As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide.
