CRBN

CRBN
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4M91, 4TZ4, 5FQD, 5HXB
Identifikatori
Aliasi	CRBN
Vanjski ID-jevi	OMIM: 609262 MGI: 1913277 HomoloGene: 9461 GeneCards: CRBN
Lokacija gena (čovjek)
Hrom.	Hromosom 3 (čovjek)
Kraj	3,179,727 bp
Lokacija gena (miš)
Hrom.	Hromosom 6 (miš)
Kraj	106,777,038 bp
Ontologija gena
Molekularna funkcija	• GO:0001948, GO:0016582 vezivanje za proteine; • vezivanje iona metala;
Ćelijska komponenta	• citoplazma; • Cul4A-RING E3 ubiquitin ligase complex; • Jedarce; • membrana; • jedro;
Biološki proces	• 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;
	Izvori:Amigo / QuickGO
Ortolozi
	51185
	58799
	ENSG00000113851
	ENSMUSG00000005362
	Q96SW2
	Q8C7D2
	NM_001173482; NM_016302
	NM_021449; NM_175357
	NP_001166953; NP_057386
	NP_067424; NP_780566
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Cereblon jest protein koji je kod ljudi kodiran genom CRBN sa hromosoma 3.^[5] Gen koji kodira cereblonski protein nalazi se na ljudskom hromozomu 3, na kratkom kraku na poziciji p26.3 od baznog para 3,190.676 do 3,221.394 bp. CRBN ortolozi su visoko konzervirani od biljaka do ljudi.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 442 aminokiseline, а molekulska težina 50.546 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MAGEGDQQDA	AHNMGNHLPL	LPAESEEEDE	MEVEDQDSKE	AKKPNIINFD
TSLPTSHTYL	GADMEEFHGR	TLHDDDSCQV	IPVLPQVMMI	LIPGQTLPLQ
LFHPQEVSMV	RNLIQKDRTF	AVLAYSNVQE	REAQFGTTAE	IYAYREEQDF
GIEIVKVKAI	GRQRFKVLEL	RTQSDGIQQA	KVQILPECVL	PSTMSAVQLE
SLNKCQIFPS	KPVSREDQCS	YKWWQKYQKR	KFHCANLTSW	PRWLYSLYDA
ETLMDRIKKQ	LREWDENLKD	DSLPSNPIDF	SYRVAACLPI	DDVLRIQLLK
IGSAIQRLRC	ELDIMNKCTS	LCCKQCQETE	ITTKNEIFSL	SLCGPMAAYV
NPHGYVHETL	TVYKACNLNL	IGRPSTEHSW	FPGYAWTVAQ	CKICASHIGW
KFTATKKDMS	PQKFWGLTRS	ALLPTIPDTE	DEISPDKVIL	CL

Funkcija

Ubikvitinacija i uloga u razvoju

Cereblon formira E3 ubikvitin-ligazni kompleks sa oštećenim DNK-vezujućim proteinom 1 (DDB1), kulinom-4A (CUL4A) i regulatorom kulina 1 (ROC1) .^[7] Ovaj kompleks ubikvitinira niz drugih proteina. Putem mehanizma koji nije u potpunosti razjašnjen, ova ubikvitinacija rezultira smanjenim nivoima faktora rasta fibroblasta 8 (FGF8) i faktora rasta fibroblasta 10 (FGF10). FGF8 zauzvrat regulira brojne razvojne procese, kao što su formiranje udova i slušnih vezikula. Konačni rezultat je da je ovaj kompleks ubikvitin-ligaze važan za izrastanje udova u embrionima.^[8]

U odsustvu cereblona, DDB1 formira kompleks sa DDB2 koji funkcioniše kao protein koji vezuje oštećenja DNK. Nadalje, cereblon i DDB2 se vezuju za DDB1 na konkurentski način.

Regulacija kalijskih kanala

Cereblon se vezuje za kalij-aktivirani kanal velike provodljivosti (KCNMA1) i regulira njegovu aktivnost.^[9]^[10] Štaviše, miševi kojima nedostaje ovaj kanal razvijaju neurološke poremećaje.^[11]

Klinički značaj

Urođene mahane

Lijek talidomid veže se za cereblon i mijenja supstrate koje može razgraditi, što dovodi do antiproliferativnog efekta na ćelije mijeloma i moguće teratogenih efekata na razvoj fetusa.^[8]^[12]^[13]^[14] Talidomid se koristio kao lijek za jutarnju mučninu od 1957. do 1961., ali je povučen s tržišta nakon što je otkriveno da uzrokuje urođene mahane.^[15] It is estimated that 10,000 to 20,000 children were affected.^[16] Međutim, ideja da je modulacija cereblona odgovorna za teratogenu aktivnost talidomida kod kokoši i zebrica dovedena je u sumnju zbog izvještaja iz 2013. da pomalidomid (potentniji analog talidomida) ne uzrokuje teratogene efekte kod ovih istih model sistema, iako se veže za cereblon jače od talidomida.^[17]^[18]

Intelektualna invalidnost

Mutacije u genu CRBN povezane su sa autosomnom recesivnom nesindromskom intelektualnom invalidnošću,^[5] vjerovatno kao posljedicom disregulacije kalcij-aktiviranih kalijumskih kanala u mozgu tokom razvoja.

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000113851 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000005362 - Ensembl, maj 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 (novembar 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.
^ "UniProt, Q96SW2" (jezik: engleski). Pristupljeno 3. 11. 2021.
^ Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N (oktobar 2006). "Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery". Nature. 443 (7111): 590–3. doi:10.1038/nature05175. PMID 16964240. S2CID 4337993.
^ ^a ^b 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. doi:10.1126/science.1177319. PMID 20223979. S2CID 17575104. Sažetak – BBC News.
^ Jo S, Lee KH, Song S, Jung YK, Park CS (septembar 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 (juli 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 (juni 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. doi:10.1073/pnas.0401702101. PMC 439001. PMID 15194823.
^ Carl Zimmer (15. 3. 2010). "Answers Begin to Emerge on How Thalidomide Caused Defects". The New York Times. Pristupljeno 21. 3. 2010. 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. 11. 3. 2010. Pristupljeno 11. 3. 2010.
^ Moisse K (11. 3. 2010). "Researchers Gain New Insights into the Mystery of Thalidomide-Caused Birth Defect". Scientific American. Pristupljeno 11. 3. 2010.
^ Anon. "Thalidomide - A Second Chance? - programme summary". BBC. Pristupljeno 1. 5. 2009.
^ Anon. "Born Freak". Happy Birthday Thalidomide. Channel 4. Pristupljeno 1. 5. 2009.
^ 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. 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.

Dopunska literatura

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. 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.

Vanjski linkovi

CRBN protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
Q96SW2

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000113851 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000005362 - Ensembl, maj 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.

[pmid15557513-5] Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP (novembar 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.

[UniProt-6] "UniProt, Q96SW2" (jezik: engleski). Pristupljeno 3. 11. 2021.

[pmid16964240-7] Angers S, Li T, Yi X, MacCoss MJ, Moon RT, Zheng N (oktobar 2006). "Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery". Nature. 443 (7111): 590–3. doi:10.1038/nature05175. PMID 16964240. S2CID 4337993.

[Ito_2010-8] 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. doi:10.1126/science.1177319. PMID 20223979. S2CID 17575104. Sažetak – BBC News.

[pmid16045448-9] Jo S, Lee KH, Song S, Jung YK, Park CS (septembar 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.

[pmid18414909-10] Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM (juli 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.

[pmid15194823-11] 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 (juni 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. doi:10.1073/pnas.0401702101. PMC 439001. PMID 15194823.

[12] Carl Zimmer (15. 3. 2010). "Answers Begin to Emerge on How Thalidomide Caused Defects". The New York Times. Pristupljeno 21. 3. 2010. As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide.

[urlThalidomide_binding_protein_revealed-13] "Thalidomide binding protein revealed". Chemistry World. Royal Society of Chemistry. 11. 3. 2010. Pristupljeno 11. 3. 2010.

[urlResearchers_Gain_New_Insights_into_the_Mystery_of_Thalidomide-Caused_Birth_Defects:_Scientific_American-14] Moisse K (11. 3. 2010). "Researchers Gain New Insights into the Mystery of Thalidomide-Caused Birth Defect". Scientific American. Pristupljeno 11. 3. 2010.

[15] Anon. "Thalidomide - A Second Chance? - programme summary". BBC. Pristupljeno 1. 5. 2009.

[Born_freak-16] Anon. "Born Freak". Happy Birthday Thalidomide. Channel 4. Pristupljeno 1. 5. 2009.

[pmid23858438-17] 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. doi:10.1073/pnas.1307684110. PMC 3732931. PMID 23858438.

[pmid22552008-18] 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.

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