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Updated: May 24, 2025

Transcriptome-Wide Profiling of Protein-RNA Interactions by Cross-Linking and Immunoprecipitation Mediated by FLAG-Biotin Tandem Purification
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Decoding Hairpin Structure Stability in Lin28-Mediated Repression

Qiang Zhu1, Limu Hu1, Chang Cui1

  • 1State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China.

Biochemistry
|February 28, 2025
PubMed

Insights

Lin28 protein inhibits let-7 microRNA (miRNA) biogenesis, impacting cancer. Molecular dynamics simulations reveal the hairpin loop is key for bypassing Lin28 repression, offering insights for cancer therapy design.

Area of Science:

  • Molecular Biology
  • Biophysics
  • Computational Chemistry

Background:

  • The Lin28 protein family is crucial in regulating microRNA (miRNA) biogenesis, particularly the let-7 family.
  • Dysregulation of the Lin28-let-7 axis is implicated in the development and progression of various cancers.
  • Understanding the molecular mechanisms of Lin28-let-7 interaction is vital for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the molecular interactions between Lin28 protein and let-7d precursor miRNA using all-atom molecular dynamics simulations.
  • To identify key structural features of let-7d responsible for Lin28 binding and repression.
  • To explore sequence-based strategies for modulating Lin28-miRNA interactions.

Main Methods:

  • All-atom molecular dynamics (MD) simulations were performed on intact and mutated let-7d precursor sequences.
  • Simulations analyzed the stability and interaction patterns between Lin28 protein domains (CSD, ZKD) and let-7d.
  • Mutagenesis studies based on let-7c-2 and statistical analysis of database information were employed.

Main Results:

  • Simulations demonstrated stable interactions between Lin28's cold shock domain (CSD) and the let-7d loop region, and its zinc knuckle domain (ZKD) with the GGAG sequence.
  • Deletion of the 3' GGAG sequence revealed the loop region is primarily responsible for bypassing Lin28 binding and repression.
  • Mutational analysis of the loop region and statistical insights indicated that terminal nucleotide interactions and middle nucleotide ring tension influence hairpin stability.

Conclusions:

  • The loop region of let-7 precursor miRNAs plays a critical role in evading Lin28-mediated repression.
  • Both terminal nucleotide interactions and internal ring tension are significant factors governing hairpin structure stability.
  • Findings provide a basis for designing novel sequences to control protein-RNA interactions, with implications for cancer therapeutics.

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