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AlphaFold-guided structural analyses of nucleosome binding proteins.

Xin Yang1,2,3, Haoqiang Zhu1,2,3, Liuxin Shi1,3

  • 1Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, BeijingĀ 100101, China.

Nucleic Acids Research
|August 12, 2025
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Summary
This summary is machine-generated.

We developed an AlphaFold-based tool to identify nucleosome-binding proteins, discovering ARID4A/B and RNF168. Dimerization of RNF168 enhances its nucleosome binding, impacting epigenetic regulation.

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Area of Science:

  • Molecular Biology
  • Epigenetics
  • Structural Biology

Background:

  • Nucleosomes are fundamental chromatin units regulating gene expression.
  • Understanding nucleosome-protein interactions is key to deciphering gene regulation.
  • Identifying novel nucleosome-binding proteins remains a challenge.

Purpose of the Study:

  • To develop and validate an AlphaFold-based algorithm for identifying nucleosome-binding proteins.
  • To discover novel proteins that bind to nucleosomes.
  • To investigate the role of protein dimerization in nucleosome binding.

Main Methods:

  • Utilized AlphaFold for structural prediction of human nuclear proteins.
  • Screened over 7600 human nuclear proteins for nucleosome-binding potential.
  • Validated predictions using known nucleosome acidic patch-binding proteins as a benchmark.
  • Employed cryogenic-electron microscopy for structural analysis of RNF168-nucleosome interactions.

Main Results:

  • Achieved a 77% prediction success rate for nucleosome-binding proteins.
  • Identified ARID4A and ARID4B as novel nucleosome-binding proteins.
  • Demonstrated that RNF168 dimerization enhances its binding affinity to nucleosomes.
  • Confirmed RNF168-nucleosome interaction structures via cryogenic-electron microscopy.

Conclusions:

  • The developed algorithm provides a rapid and effective method for discovering nucleosome-binding proteins.
  • ARID4A and ARID4B are newly identified nucleosome-binding proteins.
  • Ubiquitin E3 ligase dimerization plays a significant role in epigenetic regulation through enhanced nucleosome binding.