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Deciphering Molecular Mechanism of Histone Assembly by DNA Curtain Technique
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WDR5 Binding to Histone Serotonylation Is Driven by an Edge-Face Aromatic Interaction with Unexpected Electrostatic
Christopher R Travis1, Hanne C Henriksen1, Jake R Wilkinson1
1Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Journal of the American Chemical Society
|September 25, 2024
Summary
Researchers studied the interaction between WDR5 and histone H3, finding that van der Waals forces and edge-ring electrostatics drive this binding. This discovery clarifies previous models of this key protein-protein interaction.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Histone serotonylation is a critical post-translational modification.
- WDR5 binding to serotonylated histone H3 is linked to tumorigenesis.
Purpose of the Study:
- To investigate the edge-face aromatic interaction between WDR5 Phe149 and serotonin on H3.
- To determine the driving forces governing this key protein-protein interaction.
Main Methods:
- Genetic code expansion
- Structure-activity relationship studies
- Computational analysis
Main Results:
- The edge-face aromatic interaction is insensitive to electrostatics of the face component.
- Electron-withdrawing substituents on the edge component weaken the interaction.
- Van der Waals forces and edge-ring electrostatics govern the interaction.
Conclusions:
- This study clarifies discrepancies in previous theoretical models of edge-face aromatic interactions.
- Provides a benchmark for understanding understudied protein-protein interactions.
- Highlights the role of specific forces in histone modification-related binding events.
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