LARP1
La-srodni protein 1 (LARP1) jest protein od kDa, koji je kod ljudi kodiran genom LARP1 sa hromosoma 5.[5][6][7] LARP1 je nova sisarska meta na signalnom putu rapamicinskog kompleksa 1 (mTORC1), često hiperaktiviranog sklopa u karcinomu koji regulira rast i proliferaciju ćelija prvenstveno regulacijom sinteze proteina.[8]
Aminokiselinska sekvenca[uredi | uredi izvor]
Dužina polipeptidnog lanca je 1.096 aminokiselina, а molekulska težina 123.510 Da.[9]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MATQVEPLLP | GGATLLQAEE | HGGLVRKKPP | PAPEGKGEPG | PNDVRGGEPD | ||||
| GSARRPRPPC | AKPHKEGTGQ | QERESPRPLQ | LPGAEGPAIS | DGEEGGGEPG | ||||
| AGGGAAGAAG | AGRRDFVEAP | PPKVNPWTKN | ALPPVLTTVN | GQSPPEHSAP | ||||
| AKVVRAAVPK | QRKGSKVGDF | GDAINWPTPG | EIAHKSVQPQ | SHKPQPTRKL | ||||
| PPKKDMKEQE | KGEGSDSKES | PKTKSDESGE | EKNGDEDCQR | GGQKKKGNKH | ||||
| KWVPLQIDMK | PEVPREKLAS | RPTRPPEPRH | IPANRGEIKG | SESATYVPVA | ||||
| PPTPAWQPEI | KPEPAWHDQD | ETSSVKSDGA | GGARASFRGR | GRGRGRGRGR | ||||
| GRGGTRTHFD | YQFGYRKFDG | VEGPRTPKYM | NNITYYFDNV | SSTELYSVDQ | ||||
| ELLKDYIKRQ | IEYYFSVDNL | ERDFFLRRKM | DADGFLPITL | IASFHRVQAL | ||||
| TTDISLIFAA | LKDSKVVEIV | DEKVRRREEP | EKWPLPPIVD | YSQTDFSQLL | ||||
| NCPEFVPRQH | YQKETESAPG | SPRAVTPVPT | KTEEVSNLKT | LPKGLSASLP | ||||
| DLDSENWIEV | KKRPRPSPAR | PKKSEESRFS | HLTSLPQQLP | SQQLMSKDQD | ||||
| EQEELDFLFD | EEMEQMDGRK | NTFTAWSDEE | SDYEIDDRDV | NKILIVTQTP | ||||
| HYMRRHPGGD | RTGNHTSRAK | MSAELAKVIN | DGLFYYEQDL | WAEKFEPEYS | ||||
| QIKQEVENFK | KVNMISREQF | DTLTPEPPVD | PNQEVPPGPP | RFQQVPTDAL | ||||
| ANKLFGAPEP | STIARSLPTT | VPESPNYRNT | RTPRTPRTPQ | LKDSSQTSRF | ||||
| YPVVKEGRTL | DAKMPRKRKT | RHSSNPPLES | HVGWVMDSRE | HRPRTASISS | ||||
| SPSEGTPTVG | SYGCTPQSLP | KFQHPSHELL | KENGFTQHVY | HKYRRRCLNE | ||||
| RKRLGIGQSQ | EMNTLFRFWS | FFLRDHFNKK | MYEEFKQLAL | EDAKEGYRYG | ||||
| LECLFRYYSY | GLEKKFRLDI | FKDFQEETVK | DYEAGQLYGL | EKFWAFLKYS | ||||
| KAKNLDIDPK | LQEYLGKFRR | LEDFRVDPPM | GEEGNHKRHS | VVAGGGGGEG | ||||
| RKRCPSQSSS | RPAAMISQPP | TPPTGQPVRE | DAKWTSQHSN | TQTLGK |
Funkcija[uredi | uredi izvor]
LARP1 je najveći od sedam članova porodice proteina LARP (ostali su: LARP1B, LARP3 (poznat i kao originalni La ili SSB), LARP4A, LARP4B, LARP6 i LARP7).[10] Svi LARP oni, uključujući ljudske LARP, sadrže po dva konzervirana područja. Prva konzervirana regija dijeli homologiju s La proteinima (naziva se La motiv, dok je druga konzervirana regija (nazvana LA-motiv) ograničena na LARP proteine. LARP1 i 1B takođe sadrže konzerviranu "DM15 regiju" unutar svog C-kraja.[11] Ova regija je jedinstvena i pokazalo se da je potrebna za vezanje RNK. Mišji Larp1 eksprimiran je u dorzalnim korijenima ganglija i kičmenoj moždini, kao i u organima u razvoju koje karakteriziraju interakcije epitel-mezenhim.[6] Ljudski LARP1 prisutan je u niskim razinama u normalnim, neembrionskim ćelijama, ali je visoko izražen u epitelnim karcinomima (kao što su na jajnicima, debelom crijevu, prostati, nemaloćelijski pluća, hepatoćelijski i grliću maternice).[12][13][14][15] Neka istraživanja pokazala su da visoka razina proteina LARP1 korelira s lošijom prognozom kod pacijenata s rakom.[16][17]
LARP1 se veže i regulira translaciju terminalnih oligopirimidinskih motiva (TOP iRNK) i može direktno stupiti u interakciju s 5' kap iRNK.[18][19] Također je pokazano da stupa u interakciju s 3' krajem i kodirajućim regijama (CDS) ostalih gena.[18] LARP1 protein kolokalizira sa stresnim granulama i P-tijelima,[20] koji funkcioniraju u skladištenju i razgradnji RNK. Predloženo je da LARP1 funkcionira u P-tijelima, kako bi smanjio broj konzerviranih iRNK Ras-MAPK. Grupa homologa LARP1-a može funkcionirati u kontroli ekspresije ključnih razvojnih regulatora.[20]
Nekoliko je studija pokazalo da nedostatak LARP1 selektivno utiče na regrutiranje TOP iRNK u polisomima. U nekim ćelijamama raka, nedostatak LARP1 smanjuje proliferaciju i aktivira apoptotsku ćelijsku smrt.[14] Iako je prijavljeno smanjenje količine proteina kodiranih sa TOP iRNK u utišanim ćelijama LARP1, neki vjeruju da to može biti jednostavno objašnjeno smanjenim brojem TOP transkripata iRNK u ćelijama s nedostatkom LARP1.
Reference[uredi | uredi izvor]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000155506 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037331 - 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.
- ^ Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (oktobar 1998). "Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 5 (5): 277–86. doi:10.1093/dnares/5.5.277. PMID 9872452.
- ^ a b Chauvet S, Maurel-Zaffran C, Miassod R, Jullien N, Pradel J, Aragnol D (juli 2000). "dlarp, a new candidate Hox target in Drosophila whose orthologue in mouse is expressed at sites of epithelium/mesenchymal interactions". Developmental Dynamics. 218 (3): 401–13. doi:10.1002/1097-0177(200007)218:3<401::AID-DVDY1009>3.0.CO;2-6. PMID 10878606.
- ^ Db=gene&Cmd=ShowDetailView&TermToSearch=23367 "Entrez Gene: LARP1 La ribonucleoprotein domain family, member 1" Provjerite vrijednost parametra
|url=(pomoć). - ^ Tcherkezian J, Cargnello M, Romeo Y, Huttlin EL, Lavoie G, Gygi SP, Roux PP (Feb 2014). "Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation". Genes Dev. 28 (4): 357–71. doi:10.1101/gad.231407.113. PMC 3937514. PMID 24532714.
- ^ "UniProt, Q6PKG0" (jezik: engleski). Pristupljeno 16. 10. 2021.
- ^ Bousquet-Antonelli C, Deragon JM (maj 2009). "A comprehensive analysis of the La-motif protein superfamily". RNA. 15 (5): 750–64. doi:10.1261/rna.1478709. PMC 2673062. PMID 19299548.
- ^ Lahr RM, Mack SM, Héroux A, Blagden SP, Bousquet-Antonelli C, Deragon JM, Berman AJ (septembar 2015). "The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence". Nucleic Acids Research. 43 (16): 8077–88. doi:10.1093/nar/gkv748. PMC 4652764. PMID 26206669.
- ^ Stavraka C, Blagden S (oktobar 2015). "The La-Related Proteins, a Family with Connections to Cancer". Biomolecules. 5 (4): 2701–22. doi:10.3390/biom5042701. PMC 4693254. PMID 26501340.
- ^ Mura M, Hopkins TG, Michael T, Abd-Latip N, Weir J, Aboagye E, Mauri F, Jameson C, Sturge J, Gabra H, Bushell M, Willis AE, Curry E, Blagden SP (septembar 2015). "LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression". Oncogene. 34 (39): 5025–36. doi:10.1038/onc.2014.428. PMC 4430325. PMID 25531318.
- ^ a b Hopkins TG, Mura M, Al-Ashtal HA, Lahr RM, Abd-Latip N, Sweeney K, et al. (februar 2016). "The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer". Nucleic Acids Research. 44 (3): 1227–46. doi:10.1093/nar/gkv1515. PMC 4756840. PMID 26717985.
- ^ Xie C, Huang L, Xie S, Xie D, Zhang G, Wang P, Peng L, Gao Z (oktobar 2013). "LARP1 predict the prognosis for early-stage and AFP-normal hepatocellular carcinoma". Journal of Translational Medicine. 11: 272. doi:10.1186/1479-5876-11-272. PMC 3814951. PMID 24159927.
- ^ Ye L, Lin ST, Mi YS, Liu Y, Ma Y, Sun HM, Peng ZH, Fan JW (novembar 2016). "Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target". Tumour Biology. 37 (11): 14585–14594. doi:10.1007/s13277-016-5332-3. PMC 5126195. PMID 27614686.
- ^ Xu Z, Xu J, Lu H, Lin B, Cai S, Guo J, Zang F, Chen R (decembar 2017). "LARP1 is regulated by the XIST/miR-374a axis and functions as an oncogene in non-small cell lung carcinoma". Oncology Reports. 38 (6): 3659–3667. doi:10.3892/or.2017.6040. PMID 29039571.
- ^ a b Hong S, Freeberg MA, Han T, Kamath A, Yao Y, Fukuda T, Suzuki T, Kim JK, Inoki K (juni 2017). "LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs". eLife. 6. doi:10.7554/elife.25237. PMC 5484620. PMID 28650797.
- ^ Lahr RM, Fonseca BD, Ciotti GE, Al-Ashtal HA, Jia JJ, Niklaus MR, Blagden SP, Alain T, Berman AJ (april 2017). "La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs". eLife. 6. doi:10.7554/elife.24146. PMC 5419741. PMID 28379136.
- ^ a b Nykamp K, Lee MH, Kimble J (juli 2008). "C. elegans La-related protein, LARP-1, localizes to germline P bodies and attenuates Ras-MAPK signaling during oogenesis". RNA. 14 (7): 1378–89. doi:10.1261/rna.1066008. PMC 2441978. PMID 18515547.
Dopunska literatura[uredi | uredi izvor]
- Horke S, Reumann K, Schweizer M, Will H, Heise T (juni 2004). "Nuclear trafficking of La protein depends on a newly identified nucleolar localization signal and the ability to bind RNA". The Journal of Biological Chemistry. 279 (25): 26563–70. doi:10.1074/jbc.M401017200. PMID 15060081.
- Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (august 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–5. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
- Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T (august 2004). "Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization". Current Biology. 14 (16): 1436–50. doi:10.1016/j.cub.2004.07.051. PMID 15324660. S2CID 2371325.
- Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (oktobar 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–92. doi:10.1038/nbt1240. PMID 16964243. S2CID 14294292.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (novembar 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.