Structural Basis of Molecular Recognition of Helical Histone H3 Tail by PHD Finger Domains

Alessio Bortoluzzi, Anastasia Amato, Xavier Lucas, Manuel Blank, Alessio Ciulli (Lead / Corresponding author)

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Abstract

The plant homeodomain (PHD) fingers are amongst the largest family of epigenetic domains, first characterized as readers of methylated H3K4. Readout of histone posttranslational modifications by PHDs has been the subject of intense investigation, however less is known about the recognition of secondary structure features within histone tail itself. We solved the crystal structure of the PHD finger of the bromodomain adjacent to zinc finger 2A (BAZ2A, also known as TIP5) in complex with unmodified N-terminal histone H3 tail. The peptide is bound in a helical folded-back conformation after K4, induced by an acidic patch on the protein surface that prevents peptide binding in an extended conformation. Structural bioinformatics analyses identify a conserved Asp/Glu residue that we name “acidic wall”, found to be mutually exclusive with the conserved Trp for K4Me recognition. Neutralization or inversion of the charges at the acidic wall patch in BAZ2A, and homologous BAZ2B, weakened H3 binding. We identify simple mutations on H3 that strikingly enhance or reduce binding, as a result of their stabilization or de-stabilization of H3 helicity. Our work unravels the structural basis for binding of helical H3 tail by PHD fingers, and suggests that molecular recognition of secondary structure motifs within histone tails could represent an additional layer of regulation in epigenetic processes.
Original languageEnglish
Pages (from-to)1633-1651
Number of pages19
JournalBiochemical Journal
Volume474
Issue number10
Early online date24 Mar 2017
DOIs
Publication statusPublished - 4 May 2017

Keywords

  • epigenetics
  • PHD finger
  • reader domains
  • protein-protein interaction
  • histone binding

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    Structural studies of paired PHD finger-bromodomain chromatin-binding modules: targeting epigenetic readers with chemical probes

    Author: Amato, A., 2018

    Supervisor: Ciulli, A. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

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