Cereblon

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]

CRBN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4M91, 4TZ4, 5FQD, 5HXB
Identifiers
Aliases	CRBN, MRT2, MRT2A, Cereblon
External IDs	OMIM: 609262; MGI: 1913277; HomoloGene: 9461; GeneCards: CRBN; OMA:CRBN - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p26.2 Start 3,144,628 bp[1] End 3,179,727 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6|6 E1 Start 106,757,162 bp[2] End 106,777,038 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon Brodmann area 23 skin of hip biceps brachii endothelial cell Skeletal muscle tissue of biceps brachii superficial temporal artery tail of epididymis middle temporal gyrus corpus callosum Top expressed in pontine nuclei spermatocyte medial vestibular nucleus medial dorsal nucleus dorsal tegmental nucleus lobe of cerebellum ventral tegmental area Region I of hippocampus proper mammillary body epithelium of small intestine More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding metal ion binding Cellular component cytoplasm Cul4A-RING E3 ubiquitin ligase complex nucleolus membrane nucleus Biological process negative regulation of protein homooligomerization positive regulation of protein homodimerization activity protein ubiquitination proteasome-mediated ubiquitin-dependent protein catabolic process negative regulation of ion transmembrane transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51185 58799 Ensembl ENSG00000113851 ENSMUSG00000005362 UniProt Q96SW2 Q8C7D2 RefSeq (mRNA) NM_001173482 NM_016302 NM_021449 NM_175357 RefSeq (protein) NP_001166953 NP_057386 NP_067424 NP_780566 Location (UCSC) Chr 3: 3.14 – 3.18 Mb Chr 6: 106.76 – 106.78 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Ubiquitination and role in development

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]

Regulation of potassium channels

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]

Clinical significance

Birth defects

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]

Intellectual disability

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]

Targeted protein degradation

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]

References

1. GRCh38: Ensembl release 89: ENSG00000113851 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000005362 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP (November 2004). "A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation". Neurology. 63 (10): 1927–31. doi:10.1212/01.wnl.0000146196.01316.a2. PMC 1201536. PMID 15557513.
6. Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N (October 2006). "Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery". Nature. 443 (7111): 590–3. Bibcode:2006Natur.443..590A. doi:10.1038/nature05175. PMID 16964240. S2CID 4337993.
7. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (2010). "Identification of a primary target of thalidomide teratogenicity". Science. 327 (5971): 1345–1350. Bibcode:2010Sci...327.1345I. doi:10.1126/science.1177319. PMID 20223979. S2CID 17575104.
8. Jo S, Lee KH, Song S, Jung YK, Park CS (September 2005). "Identification and functional characterization of cereblon as a binding protein for large-conductance calcium-activated potassium channel in rat brain". J. Neurochem. 94 (5): 1212–24. doi:10.1111/j.1471-4159.2005.03344.x. PMID 16045448. S2CID 20578294.
9. Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM (July 2008). "Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation". Neurogenetics. 9 (3): 219–23. doi:10.1007/s10048-008-0128-2. PMID 18414909. S2CID 20729122.
10. Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, Sausbier U, Sailer CA, Feil R, Hofmann F, Korth M, Shipston MJ, Knaus HG, Wolfer DP, Pedroarena CM, Storm JF, Ruth P (June 2004). "Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency". Proc. Natl. Acad. Sci. U.S.A. 101 (25): 9474–8. Bibcode:2004PNAS..101.9474S. doi:10.1073/pnas.0401702101. PMC 439001. PMID 15194823.
11. Carl Zimmer (March 15, 2010). "Answers Begin to Emerge on How Thalidomide Caused Defects". The New York Times. Retrieved 2010-03-21. As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide.
12. "Thalidomide binding protein revealed". Chemistry World. Royal Society of Chemistry. 2010-03-11. Retrieved 2010-03-11.
13. Moisse K (2010-03-11). "Researchers Gain New Insights into the Mystery of Thalidomide-Caused Birth Defect". Scientific American. Retrieved 2010-03-11.
14. Anon. "Thalidomide - A Second Chance? - programme summary". BBC. Retrieved 2009-05-01.
15. Anon. "Born Freak". Happy Birthday Thalidomide. Channel 4. Retrieved 2009-05-01.
16. Mahony C, Erskine L, Niven J, Greig NH, Figg WD, Vargesson N (2013). "Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro". Proc. Natl. Acad. Sci. U.S.A. 110 (31): 12703–8. Bibcode:2013PNAS..11012703M. doi:10.1073/pnas.1307684110. PMC 3732931. PMID 23858438.
17. Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M, Mahmoudi A, Cathers B, Rychak E, Gaidarova S, Chen R, Schafer PH, Handa H, Daniel TO, Evans JF, Chopra R (2012). "Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide". Leukemia. 26 (11): 2326–35. doi:10.1038/leu.2012.119. PMC 3496085. PMID 22552008.
18. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE (2015-06-19). "DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation". Science. 348 (6241): 1376–1381. doi:10.1126/science.aab1433. ISSN 1095-9203. PMC 4937790. PMID 25999370.
19. Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM (2015-06-18). "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4". Chemistry & Biology. 22 (6): 755–763. doi:10.1016/j.chembiol.2015.05.009. ISSN 1879-1301. PMC 4475452. PMID 26051217.
20. Mullard A (2019-03-06). "First targeted protein degrader hits the clinic". Nature Reviews Drug Discovery. 18 (4): 237–239. doi:10.1038/d41573-019-00043-6. PMID 30936511.

Further reading

• Higgins JJ, Rosen DR, Loveless JM, et al. (2000). "A gene for nonsyndromic mental retardation maps to chromosome 3p25-pter". Neurology. 55 (3): 335–40. doi:10.1212/wnl.55.3.335. PMID 10932263. S2CID 19568703.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Xin W, Xiaohua N, Peilin C, et al. (2008). "Primary function analysis of human mental retardation related gene CRBN". Mol. Biol. Rep. 35 (2): 251–6. doi:10.1007/s11033-007-9077-3. PMID 17380424. S2CID 5810442.
• Hu RM, Han ZG, Song HD, et al. (2000). "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9543–8. Bibcode:2000PNAS...97.9543H. doi:10.1073/pnas.160270997. PMC 16901. PMID 10931946.
• Sowa ME, Bennett EJ, Gygi SP, Harper JW (2009). "Defining the Human Deubiquitinating Enzyme Interaction Landscape". Cell. 138 (2): 389–403. doi:10.1016/j.cell.2009.04.042. PMC 2716422. PMID 19615732.

External links

• CRBN protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: Q96SW2 (Protein cereblon) at the PDBe-KB.