Molecular basis for interaction of let-7 microRNAs with Lin28

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• MicroRNAs (miRNAs) are crucial regulators of gene expression.
• The let-7 miRNA family plays a key role in cell fate, pluripotency, differentiation, and transformation.
• Lin28 acts as a specific posttranscriptional inhibitor of let-7 biogenesis.

Purpose of the Study:

• To elucidate the molecular mechanism by which Lin28 inhibits let-7 biogenesis.
• To determine the structural basis for Lin28's specificity towards let-7 family members.
• To provide a molecular explanation for Lin28's regulatory role in gene expression.

Main Methods:

• X-ray crystallography to determine the structure of mouse Lin28 in complex with let-7 RNA precursors.
• NMR spectroscopy to analyze the flexibility of the linker region in Lin28.
• In vivo experiments to assess the inhibitory function of Lin28 on let-7.

Main Results:

• Crystal structures revealed that the two folded domains of Lin28 recognize distinct regions of let-7 RNA precursors.
• Lin28 binding and its structural features are sufficient for inhibiting let-7 biogenesis in vivo.
• NMR data showed that the linker connecting Lin28's domains is flexible, enabling binding to various let-7 family members.
• Protein-RNA complex formation induces specific conformations in both Lin28 and let-7, potentially impacting downstream interactions.

Conclusions:

• The study provides a detailed molecular explanation for Lin28's specificity in inhibiting let-7 microRNA production.
• A structural model for Lin28-mediated regulation of let-7 biogenesis and its implications for gene expression control is proposed.