// Workers AI · dad joke modeWhat did Cereblon say to its friend? "You're a real brain trust.
| CRBN | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Identifiers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | CRBN, MRT2, MRT2A, Cereblon | |||||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 609262; MGI: 1913277; GeneCards: CRBN | |||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Wikidata | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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]
Function
[edit]Ubiquitination and role in development
[edit]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]
At the molecular level, C-terminal cyclic imides have been identified as endogenous degrons recognized by cereblon. Cyclic imides can arise through spontaneous peptide-bond cleavage at asparagine or glutamine residues in aging proteins, and have long been observed in proteins such as α-crystallin.[8][9] In 2022, C-terminal aspartimide and aminoglutarimide residues were shown to bind the thalidomide-binding domain of cereblon and to function as degrons promoting CRBN-dependent ubiquitination and proteasomal degradation.[10][11]
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
[edit]Cereblon binds to the large-conductance calcium-activated potassium channel (KCNMA1) and regulates its activity.[12][13] Moreover, mice lacking this channel develop neurological disorders.[14]
Clinical significance
[edit]Birth defects
[edit]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][15][16][17] 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.[18] It is estimated that 10,000 to 20,000 children were affected.[19] 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.[20][21]
Intellectual disability
[edit]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
[edit]Based on the finding that thalidomide and related analogues bind CRBN, heterobifunctional molecules were designed linking thalidomide to ligands for other proteins of interest.[22][23] 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.[24]
References
[edit]- 1 2 3 GRCh38: Ensembl release 89: ENSG00000113851 – Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005362 – Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 1 2 3 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): 1927–1931. doi:10.1212/01.wnl.0000146196.01316.a2. PMC 1201536. PMID 15557513.
- ↑ 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): 590–593. Bibcode:2006Natur.443..590A. doi:10.1038/nature05175. PMID 16964240. S2CID 4337993.
- 1 2 3 4 Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. (2010). "Identification of a primary target of thalidomide teratogenicity". Science. 327 (5971). New York, N.Y.: 1345–1350. Bibcode:2010Sci...327.1345I. doi:10.1126/science.1177319. PMID 20223979. S2CID 17575104.
- ↑ Voorter CE, de Haard-Hoekman WA, van den Oetelaar PJ, Bloemendal H, de Jong WW (December 1988). "Spontaneous peptide bond cleavage in aging alpha-crystallin through a succinimide intermediate". The Journal of Biological Chemistry. 263 (35): 19020–19023. doi:10.1016/S0021-9258(18)37383-6. PMID 3198609.
- ↑ Friedrich MG, Wang Z, Schey KL, Truscott RJ (December 2019). "Mechanism of protein cleavage at asparagine leading to protein-protein cross-links". The Biochemical Journal. 476 (24): 3817–3834. doi:10.1042/BCJ20190743. PMC 7156126. PMID 31794011.
- ↑ Ichikawa S, Flaxman HA, Xu W, Vallavoju N, Lloyd HC, Wang B, et al. (October 2022). "The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron". Nature. 610 (7933): 775–782. Bibcode:2022Natur.610..775I. doi:10.1038/s41586-022-05333-5. PMC 10316063. PMID 36261529.
- ↑ Heim C, Spring AK, Kirchgäßner S, Schwarzer D, Hartmann MD (December 2022). "Identification and structural basis of C-terminal cyclic imides as natural degrons for cereblon". Biochemical and Biophysical Research Communications. 637: 66–72. Bibcode:2022BBRC..637...66H. doi:10.1016/j.bbrc.2022.11.001. PMID 36375252.
- ↑ 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". Journal of Neurochemistry. 94 (5): 1212–1224. doi:10.1111/j.1471-4159.2005.03344.x. PMID 16045448. S2CID 20578294.
- ↑ 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): 219–223. doi:10.1007/s10048-008-0128-2. PMID 18414909. S2CID 20729122.
- ↑ Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, et al. (June 2004). "Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency". Proceedings of the National Academy of Sciences of the United States of America. 101 (25): 9474–9478. Bibcode:2004PNAS..101.9474S. doi:10.1073/pnas.0401702101. PMC 439001. PMID 15194823.
- ↑ 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.
- ↑ "Thalidomide binding protein revealed". Chemistry World. Royal Society of Chemistry. 2010-03-11. Retrieved 2010-03-11.
- ↑ Moisse K (2010-03-11). "Researchers Gain New Insights into the Mystery of Thalidomide-Caused Birth Defect". Scientific American. Retrieved 2010-03-11.
- ↑ Anon. "Thalidomide - A Second Chance? - programme summary". BBC. Retrieved 2009-05-01.
- ↑ Anon. "Born Freak". Happy Birthday Thalidomide. Channel 4. Retrieved 2009-05-01.
- ↑ 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". Proceedings of the National Academy of Sciences of the United States of America. 110 (31): 12703–12708. Bibcode:2013PNAS..11012703M. doi:10.1073/pnas.1307684110. PMC 3732931. PMID 23858438.
- ↑ Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, et al. (2012). "Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide". Leukemia. 26 (11): 2326–2335. doi:10.1038/leu.2012.119. PMC 3496085. PMID 22552008.
- ↑ Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. (June 2015). "DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation". Science. 348 (6241). New York, N.Y.: 1376–1381. doi:10.1126/science.aab1433. PMC 4937790. PMID 25999370.
- ↑ Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, et al. (June 2015). "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4". Chemistry & Biology. 22 (6): 755–763. doi:10.1016/j.chembiol.2015.05.009. PMC 4475452. PMID 26051217.
- ↑ Mullard A (March 2019). "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
[edit]- Higgins JJ, Rosen DR, Loveless JM, Clyman JC, Grau MJ (August 2000). "A gene for nonsyndromic mental retardation maps to chromosome 3p25-pter". Neurology. 55 (3): 335–340. doi:10.1212/wnl.55.3.335. PMID 10932263. S2CID 19568703.
- Xin W, Xiaohua N, Peilin C, Xin C, Yaqiong S, Qihan W (June 2008). "Primary function analysis of human mental retardation related gene CRBN". Molecular Biology Reports. 35 (2): 251–256. doi:10.1007/s11033-007-9077-3. PMID 17380424. S2CID 5810442.
- Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, et al. (August 2000). "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America. 97 (17): 9543–9548. 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
[edit]- 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.