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Structural insights for MPP8 chromodomain interaction with histone H3 lysine 9: potential effect of phosphorylation

Yanqi Chang1, John R Horton, Mark T Bedford

  • 1Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

Journal of Molecular Biology
|March 23, 2011
PubMed

Insights

M-phase phosphoprotein 8 (MPP8) specifically binds histone H3 peptides methylated at lysine 9. Structural analysis reveals MPP8

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Epigenetics

Background:

  • M-phase phosphoprotein 8 (MPP8) is a protein containing chromodomain and ankyrin repeat domains.
  • MPP8 is known to interact with histone modifications.

Purpose of the Study:

  • To determine the crystal structure of the MPP8 chromodomain in complex with a histone H3 peptide.
  • To elucidate the molecular mechanism by which MPP8 recognizes and binds to methylated histone H3 peptides.

Main Methods:

  • X-ray crystallography to determine the structure of MPP8 chromodomain bound to H3K9me3 peptide.
  • Peptide binding assays to assess affinity and specificity.
  • Molecular modeling to investigate the effect of phosphorylation.

Main Results:

  • The crystal structure reveals MPP8 chromodomain binds H3K9me3 peptide with submicromolar affinity.
  • MPP8 interacts with six histone H3 residues, distinguishing H3K9me3 from H3K27me3.
  • A hydrophobic cage formed by Phe59, Trp80, Tyr83, and Asp87 encloses the methylated lysine 9.
  • Phosphorylation of Tyr83 may regulate MPP8 binding.

Conclusions:

  • MPP8's chromodomain possesses a specific binding pocket for H3K9me3.
  • The structural insights explain MPP8's specificity for H3K9me3 over H3K27me3.
  • Phosphorylation of MPP8, particularly at Tyr83, could serve as a regulatory mechanism for protein interactions.

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