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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'>lin28A</scene>
{{STRUCTURE_2cqf|  PDB=2cqf  |  SCENE=Sandbox_Reserved_718/Lin28a/1 }}


== '''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>  
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>  


At the molecular level, Lin28 acts as a suppressor of let-7 microRNA biogenesis.<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, 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., 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, 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., 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, 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.</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 (Balzer et al., 2010). Second, impaired glucose tolerance and insulin resistance were observed in muscle-specific Lin28a knockout mice without significant changes in the let-7 level (Zhu et al., 2011). Third, Lin28A interacts with mRNAs and cosediments with polysome in sucrose gradient centrifugation (Balzer and Moss, 2007). 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 (Polesskaya et al., 2007; Qiu et al., 2010; Xu and Huang, 2009; Xu et al., 2009).


== '''Structure''' ==
== '''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''' ==
== '''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''' ==
== '''References''' ==
{{reflist}}
{{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''' ==
== '''Contributors''' ==


Katrin Frohnmüller, Teresa Wiese
Katrin Frohnmüller, Teresa Wiese
<Structure load='2li8' size='500' frame='true' align='right' caption='pdb 2li8 crystall structure lin28A/let-7' scene='Sandbox_Reserved_718/Lin28a_let-7/1' />
<scene name='Sandbox_Reserved_718/Lin28a_let-7/1'>lin28A_let-7</scene>

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OCA, Teresa Wiese, Katrin Frohnmüller
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