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pdb 2cqf protein lin28A

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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.[1][2] 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.[3]


Structure

Lin28 consists of two domains: a cold shock domain and a pair of CCHC zinc fingers. Both are RNA binding domains. The cold-shock domain (CSD) at the N-terminal part of lin28A interacts with a loop, with a GNGAY motif, of the RNA.

The other domain has the binding element AAGNNG (most frequent sequence: AAGGAG) which can be found downstream of the GNGAY motif.

pdb 2li8 crystall structure lin28A/let-7

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The first G builds a hydrogen bond with LYS160 in the zinc finger motif. [4]

When lin28A interacts with let-7(main target), they build a complex with a crystallographic structure together.

Activity

At the molecular level, Lin28 acts as a suppressor of let-7 microRNA biogenesis.[5][6][7][8] In the nucleus, Lin28 binds to the primary transcript of let-7 (pri-let-7) and prevents its processing by RNase III DROSHA.[9][10] In the cytoplasm, it interacts with the precursor form of let-7 (pre-let-7) and interferes with pre-let-7 processing. [11][12] Lin28 recruits TUTase 4 (ZCCHC11) to induce oligo-uridylation of pre-let-7, which effectively blocks DICER processing and facilitates degradation of the RNA. [13][14][15] Lin28A is found mostly in the cytoplasmic compartment and acts in concert with TUTase 4.[16]

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. [17] Second, impaired glucose tolerance and insulin resistance were observed in muscle-specific Lin28a knockout mice without significant changes in the let-7 level.[18] Third, Lin28A interacts with mRNAs and cosediments with polysome in sucrose gradient centrifugation.[19] 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.[20][21][22][23]


Applications

References

  1. ↑ 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
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: Selective blockade of microRNA processing by Lin28. Science 320, 97–100, 2008.
  9. ↑ 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.
  10. ↑ Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: Selective blockade of microRNA processing by Lin28. Science 320, 97–100, 2008.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.


Contributors

Katrin Frohnmüller, Teresa Wiese /ref

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