Molecular Basis for Interaction of let-7 microRNAs With Lin28

Cell. 2011 Nov 23;147(5):1080-91. doi: 10.1016/j.cell.2011.10.020. Epub 2011 Nov 10.

Abstract

MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene expression. Among these, members of the let-7 miRNA family control many cell-fate determination genes to influence pluripotency, differentiation, and transformation. Lin28 is a specific, posttranscriptional inhibitor of let-7 biogenesis. We report crystal structures of mouse Lin28 in complex with sequences from let-7d, let-7-f1, and let-7 g precursors. The two folded domains of Lin28 recognize two distinct regions of the RNA and are sufficient for inhibition of let-7 in vivo. We also show by NMR spectroscopy that the linker connecting the two folded domains is flexible, accommodating Lin28 binding to diverse let-7 family members. Protein-RNA complex formation imposes specific conformations on both components that could affect downstream recognition by other processing factors. Our data provide a molecular explanation for Lin28 specificity and a model for how it regulates let-7.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Mice
  • MicroRNAs / chemistry*
  • MicroRNAs / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • RNA-Binding Proteins / chemistry*
  • RNA-Binding Proteins / metabolism
  • Sequence Alignment

Substances

  • Lin-28 protein, mouse
  • MicroRNAs
  • RNA-Binding Proteins
  • mirnlet7 microRNA, mouse

Associated data

  • PDB/3TRZ
  • PDB/3TS0
  • PDB/3TS2