Histone chaperone exploits intrinsic disorder to switch acetylation specificity

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Histones are key chromatin proteins with disordered regions prone to modification.
• Histone chaperones regulate modifying enzymes, but mechanisms for disordered substrates are unclear.
• Histone H3 lysine-acetylation is crucial for gene regulation.

Purpose of the Study:

• To elucidate how histone chaperones Asf1 and Vps75 promote H3 K9-acetylation by Rtt109.
• To understand the structural basis of histone modification on disordered substrates.

Main Methods:

• Solution structural modeling of Rtt109-Asf1-Vps75-H3:H4 complex.
• Analysis of protein-protein interactions and substrate positioning.

Main Results:

• Structural model reveals Vps75 engaging the H3 N-terminal tail via disordered interactions.
• Vps75 confines the H3 tail within the Rtt109 active site cavity.
• These 'fuzzy' interactions enable efficient lysine localization with minimal entropy loss.

Conclusions:

• Vps75's disordered C-terminal domain is critical for H3 K9-acetylation.
• Fuzzy electrostatic interactions represent a potential mechanism for modifying disordered substrates.
• This finding advances understanding of histone acetylation regulation.