Sandbox Reserved 718: Difference between revisions

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OCA, Teresa Wiese, Katrin Frohnmüller

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-<Structure load='2cqf' size='500' frame='true' align='right' caption='pdb 2cqf protein lin28A' scene='Sandbox_Reserved_718/Lin28a/1' />
+<big>'''LIN28: A RNA binding protein'''</big>
-<scene name='Sandbox_Reserved_718/Lin28a/1'>TextToBeDisplayed</scene>
+{{STRUCTURE_2cqf|  PDB=2cqf  |  SCENE=Sandbox_Reserved_718/Lin28a/1  }}
-Lin28 is a conserved cytoplasmic protein with an unusual pairing of RNA‑binding motifs: a cold shock domain and a pair of retroviral‑type CCHC zinc fingers.
-== '''Activity''' ==
+== '''Description''' ==
+Lin28 is a conserved cytoplasmic protein with an unusual pairing of RNA binding motifs: a cold shock domain and a pair of retroviral type CCHC zinc fingers. It plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, Lin28 is known to repress maturation of let-7 microRNAs and enhance translation of certain mRNAs. Mammals have two homologs, Lin28a and Lin28b. These two homologs are found from worms to humans.<ref>Jun Cho, Hyeshik Chang, S. Chul Kwon, Baekgyu Kim, Yoosik Kim, Junho Choe, Minju Ha, Yoon Ki Kim, and V. Narry Kim: ''Lin28A Is a Suppressor of ER-Associated Translation in Embryonic Stem Cells.'' In: Cell 151, S.765–777, November 9, 2012</ref><ref>Erica Balzer and Eric G. Moss: ''Localization of the Developmental Timing Regulator Lin28 to mRNP Complexes, P-bodies and Stress Granules.'' In: RNA Biology 4:1, S.16-25, January/February/March 2007.</ref> Lin28a is highly expressed in embryonic stem cells (ESCs) and was shown as one of the four factors that convert fibroblasts into induced pluripotent stem cells.<ref>Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. In: ''Induced pluripotent stem cell lines derived from human somatic cells.'' Science 318, 1917–1920, 2007.</ref>
 == '''Structure''' ==
+As mentioned above, Lin28 does consist of two domains: a cold shock domain and a <scene name='Sandbox_Reserved_718/Zfd/1'>pair of CCHC zinc fingers</scene>.
+Both are RNA binding domains. The cold-shock domain (CSD) at the N-terminal part of Lin28A, residues 37-112<ref>Loughlin, F. E., Gebert, L. F. R., Towbin, H., Brunschweiger, A., Hall, J. and Allain, F. H.-T.: ''Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28'' In: Nature Structural & Molecular Biology 19, S. 84-89, Dezember 11, 2012</ref>, interacts with a loop of the RNA, which has a GNGAY motif.
+The other domain, residues 137-176<ref>Loughlin, F. E., Gebert, L. F. R., Towbin, H., Brunschweiger, A., Hall, J. and Allain, F. H.-T.: ''Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28'' In: Nature Structural & Molecular Biology 19, S. 84-89, Dezember 11, 2012</ref>, has the binding element AAGNNG (most frequent sequence: AAGGAG) which can be found downstream of the GNGAY motif. The first G builds a <scene name='Sandbox_Reserved_718/Hydrogenbond/2'>hydrogen bond</scene> with <scene name='Sandbox_Reserved_718/Lys160/2'>LYS160</scene> in the zinc finger motif. <ref>Jun Cho, Hyeshik Chang, S. Chul Kwon, Baekgyu Kim, Yoosik Kim, Junho Choe, Minju Ha, Yoon Ki Kim, and V. Narry Kim: ''Lin28A Is a Suppressor of ER-Associated Translation in Embryonic Stem Cells.'' In: Cell 151, S.765–777, November 9, 2012</ref>
+When Lin28A interacts with <scene name='Sandbox_Reserved_718/Let-7/1'>let-7</scene>(main target), they build a complex with a crystallographic structure together.
+<Structure load='2li8' size='300' frame='true' align='left' caption='' scene='Sandbox_Reserved_718/Lin28a_let-7/1' />
+== '''Activity''' ==
+At the molecular level, Lin28 acts as a suppressor of let-7 microRNA biogenesis.<ref>Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. In: ''Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.'' Mol. Cell 32, S.276–284, 2008.</ref><ref>Newman, M.A., Thomson, J.M., and Hammond, S.M. In: ''Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.'' RNA 14, 1539–1549, 2008.</ref><ref>Rybak, A., Fuchs, H., Smirnova, L., Brandt, C., Pohl, E.E., Nitsch, R., and Wulczyn, F.G. In: ''A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment.'' Nat. Cell Biol. 10, S.987–993, 2008.</ref><ref>Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: ''Selective blockade of microRNA processing by Lin28.'' Science 320, 97–100, 2008.</ref> In the nucleus, Lin28 binds to the primary transcript of let-7 (pri-let-7) and prevents its processing by RNase III DROSHA.<ref>Newman, M.A., Thomson, J.M., and Hammond, S.M. In: ''Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.'' RNA 14, 1539–1549, 2008.</ref><ref>Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: ''Selective blockade of microRNA processing by Lin28.'' Science 320, 97–100, 2008.</ref> In the cytoplasm, it interacts with the precursor form of let-7 (pre-let-7) and interferes with pre-let-7 processing. <ref>Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. In: ''Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.'' Mol. Cell 32, S.276–284, 2008.</ref><ref>Rybak, A., Fuchs, H., Smirnova, L., Brandt, C., Pohl, E.E., Nitsch, R., and Wulczyn, F.G. In: ''A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment.'' Nat. Cell Biol. 10, S.987–993, 2008.</ref> Lin28 recruits TUTase 4 (ZCCHC11) to induce oligo-uridylation of pre-let-7, which effectively blocks DICER processing and facilitates degradation of the RNA. <ref>Hagan, J.P., Piskounova, E., and Gregory, R.I. In: ''Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells.'' Nat. Struct. Mol. Biol. 16, S.1021–1025, 2009.</ref><ref>Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. In: ''Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.'' Mol. Cell 32, S.276–284, 2008.</ref><ref>Heo, I., Joo, C., Kim, Y.K., Ha, M., Yoon, M.J., Cho, J., Yeom, K.H., Han, J., and Kim, V.N. In: ''TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.'' Cell 138, S.696–708, 2009.</ref> Lin28A is found mostly in the cytoplasmic compartment and acts in concert with TUTase 4.<ref>Piskounova, E., Polytarchou, C., Thornton, J.E., LaPierre, R.J., Pothoulakis, C., Hagan, J.P., Iliopoulos, D., and Gregory, R.I. In: ''Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms.'' Cell 147, S.1066–1079, 2011.</ref>
+Let-7 is a key target of Lin28 but there are four additional functions:
+First, during retinoic-acid-induced neurogliogenesis, Lin28a overexpression altered the expression of several transcription factors involved in early embryonic cell fate decision before any increase in let-7 level was detected. <ref>Balzer, E., Heine, C., Jiang, Q., Lee, V.M., and Moss, E.G. In: ''LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development 137, S.891–900, 2010.</ref> Second, impaired glucose tolerance and insulin resistance were observed in muscle-specific Lin28a knockout mice without significant changes in the let-7 level.<ref>Zhu, H., Shyh-Chang, N., Segre , A.V., Shinoda, G., Shah, S.P., Einhorn, W.S., Takeuchi, A., Engreitz, J.M., Hagan, J.P., Kharas, M.G., et al; DIAGRAM Consortium; MAGIC Investigators. In: ''The Lin28/let-7 axis regulates glucose metabolism.'' Cell 147, S.81–94, 2011.</ref> Third, Lin28A interacts with mRNAs and cosediments with polysome in sucrose gradient centrifugation.<ref>Erica Balzer and Eric G. Moss: ''Localization of the Developmental Timing Regulator Lin28 to mRNP Complexes, P-bodies and Stress Granules.'' In: RNA Biology 4:1, S.16-25, January/February/March 2007.</ref> Consistently, several studies reported that Lin28A can bind to and enhance translation of certain mRNAs such as Igf2 in differentiating myoblasts and Oct4 in ESCs.<ref>Polesskaya, A., Cuvellier, S., Naguibneva, I., Duquet, A., Moss, E.G., and Harel-Bellan, A. In: ''Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency.'' Genes Dev. 21, 1125–1138, 2007.</ref><ref>Qiu, C., Ma, Y., Wang, J., Peng, S., and Huang, Y. In: ''Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells.'' Nucleic Acids Res. 38, S.1240–1248, 2010.</ref><ref>Xu, B., and Huang, Y. In: ''Histone H2a mRNA interacts with Lin28 and contains a Lin28-dependent posttranscriptional regulatory element.'' Nucleic Acids Res. 37, S.4256–4263, 2009.</ref><ref>Xu, B., Zhang, K., and Huang, Y. In: ''Lin28 modulates cell growth and associates with a subset of cell cycle regulator mRNAs in mouse embryonic stem cells.'' RNA 15, S.357–361, 2009.</ref>
 == '''Applications''' ==
+Lin28 can be used as a marker of undifferntiated human embryonic stem cells<ref>PMID:14688391</ref>. It can also be used to get induced pluripotent stem cells since it is one of the four factors that can enhance the efficiency of their formation<ref>PMID:18029452</ref>.
 == '''References''' ==
+{{reflist}}
+== '''External resources''' ==
+Protein Data Bank files [http://www.rcsb.org/pdb/explore/explore.do?structureId=2cqf 2cqf] [http://www.rcsb.org/pdb/explore/explore.do?structureId=2li8 2li8]
 == '''Contributors''' ==
 Katrin Frohnmüller, Teresa Wiese
-<Structure load='Insert PDB code or filename here' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />