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Probing the Protein-Protein Interaction Between the ATRXADD Domain and the Histone H3 Tail

Angela M Zaino1, Radha Charan Dash1, M Kyle Hadden1

  • 1Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Storrs, CT 06029-3092, USA.

Molecules (Basel, Switzerland)
|March 29, 2020
PubMed

Insights

Mutations in the ATRX gene are linked to pediatric brain tumors. Researchers studied the ATRX-histone H3 interaction, finding three key binding sites essential for high-affinity binding.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Loss-of-function mutations in the *ATRX* gene are linked to pediatric brain tumors and pancreatic neuroendocrine tumors.
  • The ATRX protein's ADD domain binds to histone H3 tails, mediating chromatin localization, and is frequently mutated in these cancers.
  • The precise role of ATRX in gene regulation and cancer development requires further elucidation.

Purpose of the Study:

  • To investigate the protein-protein interaction (PPI) between the ATRX ADD domain (ATRXADD) and histone H3.
  • To experimentally validate and expand upon previous computational findings regarding the H3:ATRXADD interaction.
  • To identify critical binding regions within the H3 tail for ATRXADD.

Main Methods:

  • Development of two novel biochemical assays to study the H3:ATRXADD PPI.
  • Utilization of experimental and computational techniques to probe the interaction.
  • Analysis of the impact of mutations at specific histone H3 residues on ATRXADD binding affinity.

Main Results:

  • Demonstrated that three specific anchor points (A1, K4, and K9) in the histone H3 tail are crucial for high-affinity binding to ATRXADD.
  • Validated and extended previous computational predictions through experimental biochemical assays.
  • Established that disrupting more than one of these key contact regions is necessary for developing small molecules to inhibit the H3:ATRXADD PPI.

Conclusions:

  • The H3:ATRXADD interaction is mediated by at least three essential anchor points in the histone H3 tail.
  • The developed biochemical assays provide a robust platform for studying this critical PPI.
  • This research offers insights into ATRX function in oncogenesis and suggests strategies for therapeutic intervention targeting ATRX-mediated interactions.
Keywords:
AlphaScreen.cancerfluorescence polarizationisothermal titration calorimetryprotein-protein interactionsvirtual screening

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