Sandbox Reserved 718

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pdb 2cqf protein lin28A

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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]

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

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).

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ReferencesReferences

  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. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: Selective blockade of microRNA processing by Lin28. Science 320, 97–100, 2008.
  8. ↑ 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.
  9. ↑ Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: Selective blockade of microRNA processing by Lin28. Science 320, 97–100, 2008.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.

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Katrin Frohnmüller, Teresa Wiese

pdb 2li8 crystall structure lin28A/let-7

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OCA, Teresa Wiese, Katrin Frohnmüller
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