PCNT
Pericentrin ili kendrin, poznat i kao PCNT i pericentrin-B (PCNTB), jest protein koji je kod ljudi kodiran genom PCNT sa hromosoma 21.[3][4][5][6] Gen za ovaj protein nalazi se na centrosomu i regrutuje proteine u pericentriolski matriks (PCM), kako bi se osiguralo pravilno formiranje centrosoma i mitotskog vretena, a time i neprekinuto napredovanje ćelijskog ciklusa.[3][7][8][9][10] Njegov gen uključen je u mnoge bolesti i poremećaje, uključujući kongenitalne, kao što su mikrocefalijska osteodisplazijska primordijalna patuljastost tip II (MOPDII) i Seckelov sindrom.[7][8]
Aminokiselinska sekvenca uredi
Dužina polipeptidnog lanca je 3.336 aminokiselina, a molekulska težina 378.037 Da.[3]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MEVEQEQRRR | KVEAGRTKLA | HFRQRKTKGD | SSHSEKKTAK | RKGSAVDASV | ||||
| QEESPVTKED | SALCGGGDIC | KSTSCDDTPD | GAGGAFAAQP | EDCDGEKRED | ||||
| LEQLQQKQVN | DHPPEQCGMF | TVSDHPPEQH | GMFTVGDHPP | EQRGMFTVSD | ||||
| HPPEQHGMFT | VSDHPPEQRG | MFTISDHQPE | QRGMFTVSDH | TPEQRGIFTI | ||||
| SDHPAEQRGM | FTKECEQECE | LAITDLESGR | EDEAGLHQSQ | AVHGLELEAL | ||||
| RLSLSNMHTA | QLELTQANLQ | KEKETALTEL | REMLNSRRAQ | ELALLQSRQQ | ||||
| HELELLREQH | AREKEEVVLR | CGQEAAELKE | KLQSEMEKNA | QIVKTLKEDW | ||||
| ESEKDLCLEN | LRKELSAKHQ | SEMEDLQNQF | QKELAEQRAE | LEKIFQDKNQ | ||||
| AERALRNLES | HHQAAIEKLR | EDLQSEHGRC | LEDLEFKFKE | SEKEKQLELE | ||||
| NLQASYEDLK | AQSQEEIRRL | WSQLDSARTS | RQELSELHEQ | LLARTSRVED | ||||
| LEQLKQREKT | QHESELEQLR | IYFEKKLRDA | EKTYQEDLTL | LQQRLQGARE | ||||
| DALLDSVEVG | LSCVGLEEKP | EKGRKDHVDE | LEPERHKESL | PRFQAELEES | ||||
| HRHQLEALES | PLCIQHEGHV | SDRCCVETSA | LGHEWRLEPS | EGHSQELPWV | ||||
| HLQGVQDGDL | EADTERAARV | LGLETEHKVQ | LSLLQTELKE | EIELLKIENR | ||||
| NLYGKLQHET | RLKDDLEKVK | HNLIEDHQKE | LNNAKQKTEL | MKQEFQRKET | ||||
| DWKVMKEELQ | REAEEKLTLM | LLELREKAES | EKQTIINKFE | LREAEMRQLQ | ||||
| DQQAAQILDL | ERSLTEQQGR | LQQLEQDLTS | DDALHCSQCG | REPPTAQDGE | ||||
| LAALHVKEDC | ALQLMLARSR | FLEERKEITE | KFSAEQDAFL | QEAQEQHARE | ||||
| LQLLQERHQQ | QLLSVTAELE | ARHQAALGEL | TASLESKQGA | LLAARVAELQ | ||||
| TKHAADLGAL | ETRHLSSLDS | LESCYLSEFQ | TIREEHRQAL | ELLRADFEEQ | ||||
| LWKKDSLHQT | ILTQELEKLK | RKHEGELQSV | RDHLRTEVST | ELAGTVAHEL | ||||
| QGVHQGEFGS | EKKTALHEKE | ETLRLQSAQA | QPFHQEEKES | LSLQLQKKNH | ||||
| QVQQLKDQVL | SLSHEIEECR | SELEVLQQRR | ERENREGANL | LSMLKADVNL | ||||
| SHSERGALQD | ALRRLLGLFG | ETLRAAVTLR | SRIGERVGLC | LDDAGAGLAL | ||||
| STAPALEETW | SDVALPELDR | TLSECAEMSS | VAEISSHMRE | SFLMSPESVR | ||||
| ECEQPIRRVF | QSLSLAVDGL | MEMALDSSRQ | LEEARQIHSR | FEKEFSFKNE | ||||
| ETAQVVRKHQ | ELLECLKEES | AAKAELALEL | HKTQGTLEGF | KVETADLKEV | ||||
| LAGKEDSEHR | LVLELESLRR | QLQQAAQEQA | ALREECTRLW | SRGEATATDA | ||||
| EAREAALRKE | VEDLTKEQSE | TRKQAEKDRS | ALLSQMKILE | SELEEQLSQH | ||||
| RGCAKQAEAV | TALEQQVASL | DKHLRNQRQF | MDEQAAEREH | EREEFQQEIQ | ||||
| RLEGQLRQAA | KPQPWGPRDS | QQAPLDGEVE | LLQQKLREKL | DEFNELAIQK | ||||
| ESADRQVLMQ | EEEIKRLEEM | NINIRKKVAQ | LQEEVEKQKN | IVKGLEQDKE | ||||
| VLKKQQMSSL | LLASTLQSTL | DAGRCPEPPS | GSPPEGPEIQ | LEVTQRALLR | ||||
| RESEVLDLKE | QLEKMKGDLE | SKNEEILHLN | LKLDMQNSQT | AVSLRELEEE | ||||
| NTSLKVIYTR | SSEIEELKAT | IENLQENQKR | LQKEKAEEIE | QLHEVIEKLQ | ||||
| HELSLMGPVV | HEVSDSQAGS | LQSELLCSQA | GGPRGQALQG | ELEAALEAKE | ||||
| ALSRLLADQE | RRHSQALEAL | QQRLQGAEEA | AELQLAELER | NVALREAEVE | ||||
| DMASRIQEFE | AALKAKEATI | AERNLEIDAL | NQRKAAHSAE | LEAVLLALAR | ||||
| IRRALEQQPL | AAGAAPPELQ | WLRAQCARLS | RQLQVLHQRF | LRCQVELDRR | ||||
| QARRATAHTR | VPGAHPQPRM | DGGAKAQVTG | DVEASHDAAL | EPVVPDPQGD | ||||
| LQPVLVTLKD | APLCKQEGVM | SVLTVCQRQL | QSELLLVKNE | MRLSLEDGGK | ||||
| GKEKVLEDCQ | LPKVDLVAQV | KQLQEKLNRL | LYSMTFQNVD | AADTKSLWPM | ||||
| ASAHLLESSW | SDDSCDGEEP | DISPHIDTCD | ANTATGGVTD | VIKNQAIDAC | ||||
| DANTTPGGVT | DVIKNWDSLI | PDEMPDSPIQ | EKSECQDMSL | SSPTSVLGGS | ||||
| RHQSHTAEAG | PRKSPVGMLD | LSSWSSPEVL | RKDWTLEPWP | SLPVTPHSGA | ||||
| LSLCSADTSL | GDRADTSLPQ | TQGPGLLCSP | GVSAAALALQ | WAESPPADDH | ||||
| HVQRTAVEKD | VEDFITTSFD | SQETLSSPPP | GLEGKADRSE | KSDGSGFGAR | ||||
| LSPGSGGPEA | QTAGPVTPAS | ISGRFQPLPE | AMKEKEVRPK | HVKALLQMVR | ||||
| DESHQILALS | EGLAPPSGEP | HPPRKEDEIQ | DISLHGGKTQ | EVPTACPDWR | ||||
| GDLLQVVQEA | FEKEQEMQGV | ELQPRLSGSD | LGGHSSLLER | LEKIIREQGD | ||||
| LQEKSLEHLR | LPDRSSLLSE | IQALRAQLRM | THLQNQEKLQ | HLRTALTSAE | ||||
| ARGSQQEHQL | RRQVELLAYK | VEQEKCIAGD | LQKTLSEEQE | KANSVQKLLA | ||||
| AEQTVVRDLK | SDLCESRQKS | EQLSRSLCEV | QQEVLQLRSM | LSSKENELKA | ||||
| ALQELESEQG | KGRALQSQLE | EEQLRHLQRE | SQSAKALEEL | RASLETQRAQ | ||||
| SSRLCVALKH | EQTAKDNLQK | ELRIEHSRCE | ALLAQERSQL | SELQKDLAAE | ||||
| KSRTLELSEA | LRHERLLTEQ | LSQRTQEACV | HQDTQAHHAL | LQKLKEEKSR | ||||
| VVDLQAMLEK | VQQQALHSQQ | QLEAEAQKHC | EALRREKEVS | ATLKSTVEAL | ||||
| HTQKRELRCS | LEREREKPAW | LQAELEQSHP | RLKEQEGRKA | ARRSAEARQS | ||||
| PAAAEQWRKW | QRDKEKLREL | ELQRQRDLHK | IKQLQQTVRD | LESKDEVPGS | ||||
| RLHLGSARRA | AGSDADHLRE | QQRELEAMRQ | RLLSAARLLT | SFTSQAVDRT | ||||
| VNDWTSSNEK | AVMSLLHTLE | ELKSDLSRPT | SSQKKMAAEL | QFQFVDVLLK | ||||
| DNVSLTKALS | TVTQEKLELS | RAVSKLEKLL | KHHLQKGCSP | SRSERSAWKP | ||||
| DETAPQSSLR | RPDPGRLPPA | ASEEAHTSNV | KMEKLYLHYL | RAESFRKALI | ||||
| YQKKYLLLLI | GGFQDSEQET | LSMIAHLGVF | PSKAERKITS | RPFTRFRTAV | ||||
| RVVIAILRLR | FLVKKWQEVD | RKGALAQGKA | PRPGPRARQP | QSPPRTRESP | ||||
| PTRDVPSGHT | RDPARGRRLA | AAASPHSGGR | ATPSPNSRLE | RSLTASQDPE | ||||
| HSLTEYIHHL | EVIQQRLGGV | LPDSTSKKSC | HPMIKQ |
Struktura uredi
PCNT je protein od 360 kDa koji sadrži sekvencu domena upredene zavojnice i visoko konzervirani motiv ciljanja PCM-a zvani PACT domen, blizu svog C-terminala.[3][6][7][8][9][11][12] PACT domen odgovoran je za ciljanje proteina na centrosom i njegovo vezivanje za centriolske zidove tokom interfaza.[7][8] Osim toga, PCNT ima pet jedarnih eksportnih sekvenci koje sve doprinose njegovom jedarnom eksportu u citoplazmu, kao i jedan jedarni signal sastavljen od tri klastera aminokiselinskih baza, koje sve doprinose jedarnoj lokalizaciji proteina.[7]
PCNTB, cDNK homolog PCNT-a, identifikovali su i opisali Li et al. duz naznaku da dijele identitet sekvence od 61% i sličnost od 75%. Međutim, u poređenju sa PCNT, PCNTB sadrži dodatni domen upredene zavojnice i jedinstveni 1000-aminokiselinskih ostataka C-terminala, što sugeriše da ova dva mogu biti odvojeni proteini u novoj natporodici CPM .[6] Kao i kod PCNT-a, C-kraj PCNTB-a sadrži funkcionalne domene za lokalizaciju centriola i vezivanje CEP215. N-kraj također može sadržavati funkcionalni domen koji je povezan s domenom C-kraja, a ova asocijacija je potrebna za interakciju s centriolom.[13]
Funkcija uredi
Protein koji je kodiran ovim genom eksprimiran je u citoplazmi i centrosomu tokom cijelog ćelijskog ciklusa, a u manjoj mjeri u jedru. To je sastavni dio PCM-a, koji je centrosomska skela za učvršćivanje mikrotubula nukleacijskih kompleksa i drugih centrosomskih proteina.[3][6][7][9][13][14] U jednom modelu, PCNT kompleks je sa CEP215 i fosforiliran pomoću PLK1, što dovodi do regrutovanja i organizacije PCM komponenti, sazrijevanja centrosoma i formiranja vretena.[8][13] Protein kontrolira nukleaciju mikrotubula, interakcijom sa komponentom njihove nukleacije γ-tubulina, čime se učvršćuje γ-tubulinski kompleks prstena za centrosom, neophodan za formiranje bipolarnog vretena i sklapanje hromosoma u ranoj mitozi.[3][7][8][9][10] Ovo osigurava normalnu funkciju i organizaciju centrosoma, mitotskih vretena i citoskeleta, a dalje , regulaciju progresije ćelijskog ciklusa i kontrolnuh tačaka.[3][7][8][9][14] Smanjenje regulacije PCNT-a poremetilo je mitotičke kontrolne tačke i zadržalo ćeliju na G2/M kontrolnoj tački, što je dovelo do smrti ćelije.[12][14] Štaviše, funkcionisanje mikrotubula je takođe poremećeno, što je dovelo do mono– ili multipolarnih vretena, hromozomske neusklađenosti, preranog odvajanja sestrinskih hromatida i aneuploidije.[8][14]
PCNT je veoma bogato zastupljen u skeletnim mišićima, što ukazuje da može biti uključen u djelovanje mišićnog insulina.[9] PCNT je također uključen u razvoj neuron, interakcijom sa DISC1 za regulaciju organizacije mikrotubula.[10]
Klinički značaj uredi
Mutacije u genu "PCNT" povezane su sa Downovim sindromom (DS), dva tipa primordijalne patuljastosti, MOPDII i Seckelovim sindromom, unutarmaterničnim zaostajanjem raste, kardiomiopatijama, ranim početkom dijabetesa tip 2, hroničnom mijeloidnnom leukemijom (CML), bipolarnim afektivnim poremećajem i drugim kongenitalnim poremećajima.[7][8][10][12][13][14] Konkretno, nizak rast i mala veličina mozga karakteristična za MOPDII i Seckelov sindrom pripisuju se disfunkciji centrosoma i poremećaju rasta ćelija, kao posljedici kvara PCNT-a.[7] Dodatno, prerano starenje, cerebralna involucija, upalni i imunski odgovori su povezani sa DS-om, zbog mutacija PCNT-a, dok su teški rezistencija na insulin, dijabetes i dislipidemija predstavljeni u MOPDII povezanim s mutacijama PCNT-a.[9][12]
Interakcije uredi
Pokazalo se da PCNT ima interakcije sa:
Reference uredi
- ^ a b c GRCh38: Ensembl release 89: ENSG00000160299 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d e f g h "Entrez Gene: PCNT pericentrin (kendrin)".
- ^ Chen H, Gos A, Morris MA, Antonarakis SE (Aug 1996). "Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter". Genomics. 35 (3): 620–4. doi:10.1006/geno.1996.0411. PMID 8812505.
- ^ Flory MR, Moser MJ, Monnat RJ, Davis TN (May 2000). "Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 5919–23. Bibcode:2000PNAS...97.5919F. doi:10.1073/pnas.97.11.5919. PMC 18534. PMID 10823944.
- ^ a b c d e Li Q, Hansen D, Killilea A, Joshi HC, Palazzo RE, Balczon R (Feb 2001). "Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1". Journal of Cell Science. 114 (Pt 4): 797–809. doi:10.1242/jcs.114.4.797. PMID 11171385.
- ^ a b c d e f g h i j k l m n o p Liu Q, Yu J, Zhuo X, Jiang Q, Zhang C (Aug 2010). "Pericentrin contains five NESs and an NLS essential for its nucleocytoplasmic trafficking during the cell cycle". Cell Research. 20 (8): 948–62. doi:10.1038/cr.2010.89. PMID 20567258.
- ^ a b c d e f g h i j Kim S, Rhee K (2014). "Importance of the CEP215-pericentrin interaction for centrosome maturation during mitosis". PLOS ONE. 9 (1): e87016. Bibcode:2014PLoSO...987016K. doi:10.1371/journal.pone.0087016. PMC 3899370. PMID 24466316.
- ^ a b c d e f g Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YC, Szekeres F, Krook A, Nolan JJ, O'Driscoll M, Bober M, O'Rahilly S, Jackson AP, Semple RK (Mar 2011). "Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes". Diabetes. 60 (3): 925–35. doi:10.2337/db10-1334. PMC 3046854. PMID 21270239.
- ^ a b c d Shimizu S, Matsuzaki S, Hattori T, Kumamoto N, Miyoshi K, Katayama T, Tohyama M (Dec 2008). "DISC1-kendrin interaction is involved in centrosomal microtubule network formation". Biochemical and Biophysical Research Communications. 377 (4): 1051–6. doi:10.1016/j.bbrc.2008.10.100. PMID 18955030.
- ^ Gillingham AK, Munro S (Dec 2000). "The PACT domain, a conserved centrosomal targeting motif in the coiled-coil proteins AKAP450 and pericentrin". EMBO Reports. 1 (6): 524–9. doi:10.1093/embo-reports/kvd105. PMC 1083777. PMID 11263498.
- ^ a b c d Salemi M, Barone C, Romano C, Salluzzo R, Caraci F, Cantarella RA, Salluzzo MG, Drago F, Romano C, Bosco P (Nov 2013). "Pericentrin expression in Down's syndrome". Neurological Sciences. 34 (11): 2023–5. doi:10.1007/s10072-013-1529-z. PMID 23979692. S2CID 1823570.
- ^ a b c d e Lee K, Rhee K (Jul 2012). "Separase-dependent cleavage of pericentrin B is necessary and sufficient for centriole disengagement during mitosis". Cell Cycle. 11 (13): 2476–85. doi:10.4161/cc.20878. PMID 22722493.
- ^ a b c d e Unal S, Alanay Y, Cetin M, Boduroglu K, Utine E, Cormier-Daire V, Huber C, Ozsurekci Y, Kilic E, Simsek Kiper OP, Gumruk F (Feb 2014). "Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): a potential role of pericentrin in hematopoiesis". Pediatric Blood & Cancer. 61 (2): 302–5. doi:10.1002/pbc.24783. PMID 24106199. S2CID 13192693.
Dopunska literatura uredi
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- Chen H, Gos A, Morris MA, Antonarakis SE (Aug 1996). "Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter". Genomics. 35 (3): 620–4. doi:10.1006/geno.1996.0411. PMID 8812505.
- Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (Oct 1997). "Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 4 (5): 307–13. doi:10.1093/dnares/4.5.307. PMID 9455477.
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- Flory MR, Moser MJ, Monnat RJ, Davis TN (May 2000). "Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 5919–23. Bibcode:2000PNAS...97.5919F. doi:10.1073/pnas.97.11.5919. PMC 18534. PMID 10823944.
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- Li Q, Hansen D, Killilea A, Joshi HC, Palazzo RE, Balczon R (Feb 2001). "Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1". Journal of Cell Science. 114 (Pt 4): 797–809. doi:10.1242/jcs.114.4.797. PMID 11171385.
- Takahashi M, Yamagiwa A, Nishimura T, Mukai H, Ono Y (Sep 2002). "Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring gamma-tubulin ring complex". Molecular Biology of the Cell. 13 (9): 3235–45. doi:10.1091/mbc.E02-02-0112. PMC 124155. PMID 12221128.
- Flory MR, Davis TN (Sep 2003). "The centrosomal proteins pericentrin and kendrin are encoded by alternatively spliced products of one gene". Genomics. 82 (3): 401–5. doi:10.1016/S0888-7543(03)00119-8. PMID 12906865.
- Chang F, Re F, Sebastian S, Sazer S, Luban J (Apr 2004). "HIV-1 Vpr induces defects in mitosis, cytokinesis, nuclear structure, and centrosomes". Molecular Biology of the Cell. 15 (4): 1793–801. doi:10.1091/mbc.E03-09-0691. PMC 379276. PMID 14767062.
- Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M, Ogawa N (May 2004). "DISC1 localizes to the centrosome by binding to kendrin". Biochemical and Biophysical Research Communications. 317 (4): 1195–9. doi:10.1016/j.bbrc.2004.03.163. PMID 15094396.
- Jurczyk A, Gromley A, Redick S, San Agustin J, Witman G, Pazour GJ, Peters DJ, Doxsey S (Aug 2004). "Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly". The Journal of Cell Biology. 166 (5): 637–43. doi:10.1083/jcb.200405023. PMC 2172416. PMID 15337773.
- Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S (Sep 2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions". Genome Research. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC 515316. PMID 15342556.
- Golubkov VS, Chekanov AV, Doxsey SJ, Strongin AY (Dec 2005). "Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: potential implications for tumorigenesis". The Journal of Biological Chemistry. 280 (51): 42237–41. doi:10.1074/jbc.M510139200. PMID 16251193.
- Nousiainen M, Silljé HH, Sauer G, Nigg EA, Körner R (Apr 2006). "Phosphoproteome analysis of the human mitotic spindle". Proceedings of the National Academy of Sciences of the United States of America. 103 (14): 5391–6. Bibcode:2006PNAS..103.5391N. doi:10.1073/pnas.0507066103. PMC 1459365. PMID 16565220.