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Structural basis of paralog-specific KDM2A/B nucleosome recognition
Cathy J Spangler1,2, Aleksandra Skrajna3, Caroline A Foley3
1Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nature Chemical Biology
|February 16, 2023
Summary
The histone H3K36 demethylase KDM2A, unlike its paralog KDM2B, binds nucleosomes via the acidic patch. This interaction is crucial for KDM2A
Area of Science:
- Chromatin biology
- Molecular enzymology
- Epigenetics
Background:
- The nucleosome acidic patch is a key protein interaction site on chromatin.
- Understanding how proteins recognize the acidic patch is vital for chromatin regulation.
- Histone demethylases play critical roles in gene transcription and disease.
Purpose of the Study:
- To elucidate the molecular mechanisms of acidic patch recognition by histone demethylases.
- To investigate the nucleosome binding specificity of KDM2A and KDM2B.
Main Methods:
- Amino acid resolution acidic patch interactome screening.
- Cryogenic electron microscopy (cryo-EM) structure determination.
- Biochemical assays to study enzyme-nucleosome interactions.
Main Results:
- KDM2A, but not KDM2B, requires the acidic patch for nucleosome binding.
- Cryo-EM structures reveal paralog-specific KDM2-nucleosome interactions.
- Nucleosomal DNA unwrapping and histone charge shielding facilitate H3K36 accessibility for demethylation.
Conclusions:
- Acidic patch recognition is a critical determinant of KDM2A nucleosome binding specificity.
- Structural insights into KDM2A/B-nucleosome complexes illuminate mechanisms of histone demethylation.
- These findings advance understanding of epigenetic regulation by JumonjiC domain demethylases.
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