Why do histone monomethylation and dimethylation cause a significant difference in binding to LEDGF?

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• Lens epithelium-derived growth factor (LEDGF) is a chromatin-binding protein involved in gene transcription.
• LEDGF is implicated in diseases such as acquired immunodeficiency syndrome (AIDS) and various cancers.
• The PWWP domain of LEDGF specifically interacts with histone H3 at lysine 36 (H3K36).

Purpose of the Study:

• To investigate the dependency of LEDGF PWWP domain binding affinity on the methylation state of H3K36.
• To elucidate the molecular mechanisms underlying the interaction between LEDGF PWWP and methylated H3K36.

Main Methods:

• Molecular dynamics simulations were employed.
• Simulations involved the LEDGF PWWP domain and histone H3 fragments with varying H3K36 methylation states (nonmethylated, monomethylated, dimethylated, trimethylated).

Main Results:

• Both hydrophobic and electrostatic interactions are critical for LEDGF PWWP domain binding to H3K36.
• Binding is unstable with nonmethylated and monomethylated H3K36 due to hydrogen bonding with water molecules.
• Dimethylated and trimethylated H3K36 exhibit stable binding as they do not form these water-mediated hydrogen bonds.

Conclusions:

• The methylation state of H3K36 significantly influences the stability of LEDGF PWWP domain binding.
• Specific methylation patterns (di- and trimethylation) stabilize the interaction, suggesting a role in regulating gene transcription in health and disease contexts.