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Fe2+-Sensing α-Synuclein Iron-Responsive Messenger RNA/eIF4F Complex Binding and Regulating mRNA Translation

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  • 1Department of Life Sciences, College of Science & General Studies, Alfaisal University, Riyadh 11533, Saudi Arabia.

International Journal of Molecular Sciences
|October 16, 2025
PubMed
Summary

Iron enhances alpha-synuclein (α-Syn) mRNA translation by increasing the binding affinity between the α-Syn iron-responsive element (IRE) and the eIF4F translation factor. This study reveals iron

Keywords:
IRP1Parkinson’s diseasebindingeIF4Ffluorescenceprotein synthesisthermodynamicsα-Syn IRE

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Alpha-synuclein (α-Syn) protein is implicated in Parkinson's disease (PD) pathogenesis.
  • The 5'-untranslated region (5'-UTR) of α-Syn mRNA contains a structured iron-responsive element (IRE) that regulates translation.
  • Iron (Fe2+) influences protein synthesis rates via IRE mRNA.

Purpose of the Study:

  • To elucidate the interaction mechanism between the α-Syn IRE and the eukaryotic translation initiation factor 4F (eIF4F).
  • To establish a quantitative relationship between the binding affinity of α-Syn IRE with eIF4F and its translation efficiency.
  • To investigate the modulatory effect of Fe2+ on this interaction and its impact on α-Syn translation.

Main Methods:

  • Fluorescence-based binding assays to determine the binding affinity (Ka) between α-Syn IRE and eIF4F.
  • Temperature-dependent studies (10-30 °C) to analyze binding kinetics (Kd) with and without Fe2+.
  • Thermodynamic analyses to understand the binding energetics and forces involved (van der Waals, hydrogen bonding).
  • Experiments involving depleted lysates and exogenous addition of eIF4F to assess functional restoration of α-Syn protein synthesis.

Main Results:

  • Demonstrated strong binding affinity between α-Syn IRE and eIF4F (Ka = 8.4 × 10^6 M^-1 at 25 °C).
  • Showed that Fe2+ significantly enhances (~three-fold) the binding affinity of α-Syn IRE with eIF4F, outcompeting IRP1 binding.
  • Thermodynamic analysis indicated spontaneous binding driven by van der Waals and hydrogen bonding, with Fe2+ further stabilizing the complex.
  • Confirmed that eIF4F restores α-Syn translation in depleted lysates, and Fe2+ boosts this process.
  • Observed that IRP1 represses α-Syn translation, but Fe2+ reverses this by promoting eIF4F binding and reducing IRP1 binding.

Conclusions:

  • Iron plays a critical role in regulating α-synuclein mRNA translation.
  • The interaction between α-Syn IRE and eIF4F is a key regulatory step modulated by iron.
  • Fe2+ acts as a potent enhancer of α-Syn mRNA translation by stabilizing the eIF4F complex and modulating IRP1 activity.