Cereblon is a protein that in humans is encoded by the CRBNgene.[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. 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 channelsedit
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 significanceedit
Birth defectsedit
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fetal development.[7][11][12][13] Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects.[14] It is estimated that 10,000 to 20,000 children were affected.[15] However, the idea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 disabilityedit
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 degradationedit
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]
Referencesedit
^ abcGRCh38: Ensembl release 89: ENSG00000113851 - Ensembl, May 2017
^ abcGRCm38: 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.
^ abcHiggins 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. PMC1201536. 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): 590–3. Bibcode:2006Natur.443..590A. doi:10.1038/nature05175. PMID 16964240. S2CID 4337993.
^ abcdIto 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.
^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.
^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.
^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. PMC439001. 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.
^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. PMC3732931. PMID 23858438.
^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. PMC3496085. PMID 22552008.
^Winter, Georg E.; Buckley, Dennis L.; Paulk, Joshiawa; Roberts, Justin M.; Souza, Amanda; Dhe-Paganon, Sirano; Bradner, James E. (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. PMC4937790. PMID 25999370.
^Lu, Jing; Qian, Yimin; Altieri, Martha; Dong, Hanqing; Wang, Jing; Raina, Kanak; Hines, John; Winkler, James D.; Crew, Andrew P.; Coleman, Kevin; Crews, Craig M. (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. PMC4475452. PMID 26051217.
^Mullard, Asher (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.
Further readingedit
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. PMC16901. PMID 10931946.
Overview of all the structural information available in the PDB for UniProt: Q96SW2 (Protein cereblon) at the PDBe-KB.
November 01, 2023
cereblon, protein, that, humans, encoded, crbn, gene, gene, that, encodes, cereblon, protein, found, human, chromosome, short, position, from, base, pair, base, pair, crbn, orthologs, highly, conserved, from, plants, humans, crbnavailable, structurespdbortholo. 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 CRBNAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes4M91 4TZ4 5FQD 5HXBIdentifiersAliasesCRBN MRT2 MRT2A CereblonExternal IDsOMIM 609262 MGI 1913277 HomoloGene 9461 GeneCards CRBNGene location Human Chr Chromosome 3 human 1 Band3p26 2Start3 144 628 bp 1 End3 179 727 bp 1 Gene location Mouse Chr Chromosome 6 mouse 2 Band6 6 E1Start106 757 162 bp 2 End106 777 038 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inAchilles tendonBrodmann area 23biceps brachiiendothelial cellsuperficial temporal arterymiddle temporal gyruscorpus callosumpostcentral gyrusparietal pleurasuperior frontal gyrusTop expressed inpontine nucleispermatocytemedial vestibular nucleusmedial dorsal nucleusdorsal tegmental nucleusventral tegmental areaRegion I of hippocampus propermammillary bodyfacial motor nucleuslateral hypothalamusMore reference expression dataBioGPSn aGene ontologyMolecular functionprotein binding metal ion bindingCellular componentcytoplasm Cul4A RING E3 ubiquitin ligase complex nucleolus membrane nucleusBiological processnegative regulation of protein homooligomerization positive regulation of protein homodimerization activity protein ubiquitination proteasome mediated ubiquitin dependent protein catabolic process negative regulation of ion transmembrane transportSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez5118558799EnsemblENSG00000113851ENSMUSG00000005362UniProtQ96SW2Q8C7D2RefSeq mRNA NM 001173482NM 016302NM 021449NM 175357RefSeq protein NP 001166953NP 057386NP 067424NP 780566Location UCSC Chr 3 3 14 3 18 MbChr 6 106 76 106 78 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 1 1 Ubiquitination and role in development 1 2 Regulation of potassium channels 2 Clinical significance 2 1 Birth defects 2 2 Intellectual disability 2 3 Targeted protein degradation 3 References 4 Further reading 5 External linksFunction editUbiquitination 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 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 edit 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 editBirth 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 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 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 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 edit a b c GRCh38 Ensembl release 89 ENSG00000113851 Ensembl May 2017 a b c 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 a b c 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 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 a b c d 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 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 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 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 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 Proc Natl Acad Sci U S A 110 31 12703 8 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 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 Winter Georg E Buckley Dennis L Paulk Joshiawa Roberts Justin M Souza Amanda Dhe Paganon Sirano Bradner James E 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 Lu Jing Qian Yimin Altieri Martha Dong Hanqing Wang Jing Raina Kanak Hines John Winkler James D Crew Andrew P Coleman Kevin Crews Craig M 2015 06 18 Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4 Chemistry amp Biology 22 6 755 763 doi 10 1016 j chembiol 2015 05 009 ISSN 1879 1301 PMC 4475452 PMID 26051217 Mullard Asher 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 Further reading editHiggins 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 editCRBN 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 Retrieved from https en wikipedia org w index php title Cereblon amp oldid 1170693380, wikipedia, wiki, book, books, library,
