NIPBL

Bradavicoliki protein-B (NIPBL), znan i kao SCC2 ili delangin jest protein koji je kod ljudi kodiran genom NIPBL sa hromosoma 5.^[5] NIPBL je potreban za povezivanje kohezina s DNK i glavna je podjedinica kompleksa za punjenje kohezina.^[6] Heterozigotne mutacije u NIPBL čine oko 60% slučajeva sindroma Cornelije de Lange.^[7]

NIPBL
Identifikatori
Aliasi	NIPBL
Vanjski ID-jevi	OMIM: 608667 MGI: 1913976 HomoloGene: 15850 GeneCards: NIPBL
Lokacija gena (čovjek) Hrom. Hromosom 5 (čovjek)[1] Bend 5p13.2 Početak 36,876,769 bp[1] Kraj 37,066,413 bp[1]
Lokacija gena (miš) Hrom. Hromosom 15 (miš)[2] Bend 15|15 A1 Početak 8,320,101 bp[2] Kraj 8,473,947 bp[2]
Ontologija gena Molekularna funkcija • mediator complex binding • chromo shadow domain binding • protein N-terminus binding • histone deacetylase binding • chromatin binding • protein C-terminus binding • GO:0001948, GO:0016582 vezivanje za proteine Ćelijska komponenta • SMC loading complex • nukleoplazma • Hromatin • Egzosom • jedro • integrator complex • nuclear chromosome • hromosom • Scc2-Scc4 cohesin loading complex Biološki proces • positive regulation of histone deacetylation • forelimb morphogenesis • eye morphogenesis • regulation of embryonic development • kognitivna funkcija • uterus morphogenesis • cellular response to X-ray • regulation of developmental growth • heart morphogenesis • outflow tract morphogenesis • positive regulation of ossification • GO:1901227 negative regulation of transcription by RNA polymerase II • sluh • cellular response to DNA damage stimulus • stem cell population maintenance • ear morphogenesis • heart development • brain development • developmental growth • external genitalia morphogenesis • regulation of hair cycle • positive regulation of multicellular organism growth • embryonic digestive tract morphogenesis • gall bladder development • Regulacija ekspresije gena • embryonic cranial skeleton morphogenesis • embryonic viscerocranium morphogenesis • ćelijski ciklus • metanephros development • GO:0045996 negative regulation of transcription, DNA-templated • fat cell differentiation • maintenance of mitotic sister chromatid cohesion • embryonic forelimb morphogenesis • face morphogenesis • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II • positive regulation of neuron migration • transcription, DNA-templated • GO:0009373 regulation of transcription, DNA-templated • multicellular organism development • mitotic sister chromatid cohesion • double-strand break repair • mitotic chromosome condensation • establishment of mitotic sister chromatid cohesion • rDNA condensation • establishment of protein localization to chromatin • cohesin loading • positive regulation of mitotic cohesin loading • Razmjena sestrinskih hromatida Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	25836	71175
Ensembl	ENSG00000164190	ENSMUSG00000022141
UniProt	Q6KC79	Q6KCD5
RefSeq (mRNK)	NM_015384 NM_133433	NM_027707 NM_201232
RefSeq (bjelančevina)	NP_056199 NP_597677	NP_081983 NP_957684
Lokacija (UCSC)	Chr 5: 36.88 – 37.07 Mb	Chr 15: 8.32 – 8.47 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 2.804 aminokiseline, а molekulska težina 316.051 Da.^[8].

• 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
MNGDMPHVPI		TTLAGIASLT		DLLNQLPLPS		PLPATTTKSL		LFNARIAEEV
NCLLACRDDN		LVSQLVHSLN		QVSTDHIELK		DNLGSDDPEG		DIPVLLQAVL
ARSPNVFREK		SMQNRYVQSG		MMMSQYKLSQ		NSMHSSPASS		NYQQTTISHS
PSSRFVPPQT		SSGNRFMPQQ		NSPVPSPYAP		QSPAGYMPYS		HPSSYTTHPQ
MQQASVSSPI		VAGGLRNIHD		NKVSGPLSGN		SANHHADNPR		HGSSEDYLHM
VHRLSSDDGD		SSTMRNAASF		PLRSPQPVCS		PAGSEGTPKG		SRPPLILQSQ
SLPCSSPRDV		PPDILLDSPE		RKQKKQKKMK		LGKDEKEQSE		KAAMYDIISS
PSKDSTKLTL		RLSRVRSSDM		DQQEDMISGV		ENSNVSENDI		PFNVQYPGQT
SKTPITPQDI		NRPLNAAQCL		SQQEQTAFLP		ANQVPVLQQN		TSVAAKQPQT
SVVQNQQQIS		QQGPIYDEVE		LDALAEIERI		ERESAIERER		FSKEVQDKDK
PLKKRKQDSY		PQEAGGATGG		NRPASQETGS		TGNGSRPALM		VSIDLHQAGR
VDSQASITQD		SDSIKKPEEI		KQCNDAPVSV		LQEDIVGSLK		STPENHPETP
KKKSDPELSK		SEMKQSESRL		AESKPNENRL		VETKSSENKL		ETKVETQTEE
LKQNESRTTE		CKQNESTIVE		PKQNENRLSD		TKPNDNKQNN		GRSETTKSRP
ETPKQKGESR		PETPKQKSDG		HPETPKQKGD		GRPETPKQKG		ESRPETPKQK
NEGRPETPKH		RHDNRRDSGK		PSTEKKPEVS		KHKQDTKSDS		PRLKSERAEA
LKQRPDGRSV		SESLRRDHDN		KQKSDDRGES		ERHRGDQSRV		RRPETLRSSS
RNEHGIKSDS		SKTDKLERKH		RHESGDSRER		PSSGEQKSRP		DSPRVKQGDS
NKSRSDKLGF		KSPTSKDDKR		TEGNKSKVDT		NKAHPDNKAE		FPSYLLGGRS
GALKNFVIPK		IKRDKDGNVT		QETKKMEMKG		EPKDKVEKIG		LVEDLNKGAK
PVVVLQKLSL		DDVQKLIKDR		EDKSRSSLKP		IKNKPSKSNK		GSIDQSVLKE
LPPELLAEIE		STMPLCERVK		MNKRKRSTVN		EKPKYAEISS		DEDNDSDEAF
ESSRKRHKKD		DDKAWEYEER		DRRSSGDHRR		SGHSHEGRRS		SGGGRYRNRS
PSDSDMEDYS		PPPSLSEVAR		KMKKKEKQKK		RKAYEPKLTP		EEMMDSSTFK
RFTASIENIL		DNLEDMDFTA		FGDDDEIPQE		LLLGKHQLNE		LGSESAKIKA
MGIMDKLSTD		KTVKVLNILE		KNIQDGSKLS		TLLNHNNDTE		EEERLWRDLI
MERVTKSADA		CLTTINIMTS		PNMPKAVYIE		DVIERVIQYT		KFHLQNTLYP
QYDPVYRLDP		HGGGLLSSKA		KRAKCSTHKQ		RVIVMLYNKV		CDIVSSLSEL
LEIQLLTDTT		ILQVSSMGIT		PFFVENVSEL		QLCAIKLVTA		VFSRYEKHRQ
LILEEIFTSL		ARLPTSKRSL		RNFRLNSSDM		DGEPMYIQMV		TALVLQLIQC
VVHLPSSEKD		SNAEEDSNKK		IDQDVVITNS		YETAMRTAQN		FLSIFLKKCG
SKQGEEDYRP		LFENFVQDLL		STVNKPEWPA		AELLLSLLGR		LLVHQFSNKS
TEMALRVASL		DYLGTVAARL		RKDAVTSKMD		QGSIERILKQ		VSGGEDEIQQ
LQKALLDYLD		ENTETDPSLV		FSRKFYIAQW		FRDTTLETEK		AMKSQKDEES
SEGTHHAKEI		ETTGQIMHRA		ENRKKFLRSI		IKTTPSQFST		LKMNSDTVDY
DDACLIVRYL		ASMRPFAQSF		DIYLTQILRV		LGENAIAVRT		KAMKCLSEVV
AVDPSILARL		DMQRGVHGRL		MDNSTSVREA		AVELLGRFVL		CRPQLAEQYY
DMLIERILDT		GISVRKRVIK		ILRDICIEQP		TFPKITEMCV		KMIRRVNDEE
GIKKLVNETF		QKLWFTPTPH		NDKEAMTRKI		LNITDVVAAC		RDTGYDWFEQ
LLQNLLKSEE		DSSYKPVKKA		CTQLVDNLVE		HILKYEESLA		DSDNKGVNSG
RLVACITTLF		LFSKIRPQLM		VKHAMTMQPY		LTTKCSTQND		FMVICNVAKI
LELVVPLMEH		PSETFLATIE		EDLMKLIIKY		GMTVVQHCVS		CLGAVVNKVT
QNFKFVWACF		NRYYGAISKL		KSQHQEDPNN		TSLLTNKPAL		LRSLFTVGAL
CRHFDFDLED		FKGNSKVNIK		DKVLELLMYF		TKHSDEEVQT		KAIIGLGFAF
IQHPSLMFEQ		EVKNLYNNIL		SDKNSSVNLK		IQVLKNLQTY		LQEEDTRMQQ
ADRDWKKVAK		QEDLKEMGDV		SSGMSSSIMQ		LYLKQVLEAF		FHTQSSVRHF
ALNVIALTLN		QGLIHPVQCV		PYLIAMGTDP		EPAMRNKADQ		QLVEIDKKYA
GFIHMKAVAG		MKMSYQVQQA		INTCLKDPVR		GFRQDESSSA		LCSHLYSMIR
GNRQHRRAFL		ISLLNLFDDT		AKTDVTMLLY		IADNLACFPY		QTQEEPLFIM
HHIDITLSVS		GSNLLQSFKE		SMVKDKRKER		KSSPSKENES		SDSEEEVSRP
RKSRKRVDSD		SDSDSEDDIN		SVMKCLPENS		APLIEFANVS		QGILLLLMLK
QHLKNLCGFS		DSKIQKYSPS		ESAKVYDKAI		NRKTGVHFHP		KQTLDFLRSD
MANSKITEEV		KRSIVKQYLD		FKLLMEHLDP		DEEEEEGEVS		ASTNARNKAI
TSLLGGGSPK		NNTAAETEDD		ESDGEDRGGG		TSGSLRRSKR		NSDSTELAAQ
MNESVDVMDV		IAICCPKYKD		RPQIARVVQK		TSSGFSVQWM		AGSYSGSWTE
AKRRDGRKLV		PWVDTIKESD		IIYKKIALTS		ANKLTNKVVQ		TLRSLYAAKD
GTSS

Struktura i interakcije

Struktura SCC4 (zeleno) u kompleksu sa N-terminalnim domenom SCC2 (plavo) pupajučeg kvasca (Hinshaw et al., 2015)

NIPBL je veliki kukasti protein koji sadrži HEAT-ponavljanje.^[9] Formira kompleks sa MAU2 (SCC4 u pupajućem kvascu), poznat kao kompleks kohezinskog utovara.^[10] Kako ovo ime sugerira, NiPBL i MAU2 potrebni su za početno udruženje kohezina sa DNK.

Smatra se da kohezin posreduje interakcije poboljšavač-promotor i generira topološki udružujuće domene (TADS) kao i posredovanje kohezije i reguliranje arhitekture DNK. Kompleks kohezina potreban je za popravak DNK homolognom rekombinacijom. S obzirom da je NIPBL potreban za udruživanje kohezina s DNK, smatra se da je i NiPBL potreban za sve ove procese. Dosljedno, inaktivacija NiPBL-a rezultira u topološkom udruživanju gubitaka i kohezije.^[11]

NIPBL se dinamički veže na hromatin, glavnim putem udruživanja sa kohezinom.^[12] Kretanje NiPBL-a unutar hromatina u skladu je sa mehanizmom koji uključuje skakanje između hromosomkog koheziranja prstenova. Pokazana je i kohezina nezavisna regulacijia ekspresija odgovornog gena.^[13][14]

Klinički značaj

Mutacije u ovom genu rezultiraju sindromom Cornelije de Lange (CDLS), poremećaj koji karakterizira dismorfne karakteristike lica, kašnjenje rasta, smanjenje dužine udova i mentalna invalidnost^[5] kao što su ove mutacije. Obično su heterozigotni CD-ovi pogođeni smanjenjem NiPBL-a nije potpuni gubitak. Eksperimenti na ćelijama pacijenata i miševa pokazuju da je smanjenje za manje od polovine.^[15] Nije poznato zašto se javlja smanjenje ekspresije NIPBL u CDL-ovima.

Reference

1. GRCh38: Ensembl release 89: ENSG00000164190 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022141 - 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.
5. "Entrez Gene: Nipped-B homolog (Drosophila)".
6. Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (2000). "Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins". Molecular Cell. 5 (2): 243–54. doi:10.1016/S1097-2765(00)80420-7. PMID 10882066.
7. Rohatgi S, Clark D, Kline AD, Jackson LG, Pie J, Siu V, Ramos FJ, Krantz ID, Deardorff MA (juli 2010). "Facial diagnosis of mild and variant CdLS: Insights from a dysmorphologist survey". American Journal of Medical Genetics. Part A. 152A (7): 1641–53. doi:10.1002/ajmg.a.33441. PMC 4133091. PMID 20583156.
8. "UniProt, Q6KC79" (jezik: engleski). Pristupljeno 17. 10. 2021.
9. Kikuchi S, Borek DM, Otwinowski Z, Tomchick DR, Yu H (novembar 2016). "Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy". Proceedings of the National Academy of Sciences of the United States of America. 113 (44): 12444–12449. doi:10.1073/pnas.1611333113. PMC 5098657. PMID 27791135.
10. Nasmyth K (oktobar 2011). "Cohesin: a catenase with separate entry and exit gates?". Nature Cell Biology. 13 (10): 1170–7. doi:10.1038/ncb2349. PMID 21968990. S2CID 25382204.
11. Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, Nasmyth K (februar 2000). "Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins". Molecular Cell. 5 (2): 243–54. doi:10.1016/s1097-2765(00)80420-7. PMID 10882066.
12. Rhodes J, Mazza D, Nasmyth K, Uphoff S (2017). "Scc2/Nipbl hops between chromosomal cohesin rings after loading". eLife. 6. doi:10.7554/eLife.30000. PMC 5621834. PMID 28914604.
13. Zuin J, Franke V, van Ijcken WF, van der Sloot A, Krantz ID, van der Reijden MI, Nakato R, Lenhard B, Wendt KS (februar 2014). "A cohesin-independent role for NIPBL at promoters provides insights in CdLS". PLOS Genetics. 10 (2): e1004153. doi:10.1371/journal.pgen.1004153. PMC 3923681. PMID 24550742.
14. van den Berg DL, Azzarelli R, Oishi K, Martynoga B, Urbán N, Dekkers DH, Demmers JA, Guillemot F (januar 2017). "Nipbl Interacts with Zfp609 and the Integrator Complex to Regulate Cortical Neuron Migration". Neuron. 93 (2): 348–361. doi:10.1016/j.neuron.2016.11.047. PMC 5263256. PMID 28041881.
15. Kawauchi S, Calof AL, Santos R, Lopez-Burks ME, Young CM, Hoang MP, Chua A, Lao T, Lechner MS, Daniel JA, Nussenzweig A, Kitzes L, Yokomori K, Hallgrimsson B, Lander AD (septembar 2009). "Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome". PLOS Genetics. 5 (9): e1000650. doi:10.1371/journal.pgen.1000650. PMC 2730539. PMID 19763162.

Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.