Sandbox Reserved 718: Difference between revisions
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< | <big>'''LIN28: A RNA binding protein'''</big> | ||
{{STRUCTURE_2cqf| PDB=2cqf | SCENE=Sandbox_Reserved_718/Lin28a/1 }} | |||
== '''Description''' == | == '''Description''' == | ||
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== '''Structure''' == | == '''Structure''' == | ||
Lin28 | 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 | 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 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 | 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''' == | == '''Activity''' == | ||
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Let-7 is a key target of Lin28 but there are four additional functions: | 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> | 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 | ||