Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• CBP and p300 are crucial histone acetyltransferases (HATs) involved in gene regulation.
• Mutations in their catalytic cores are implicated in various genetic disorders, including cancer.

Purpose of the Study:

• To elucidate the structural basis of p300 catalytic core function and regulation.
• To understand the role of specific domains in p300 activity and disease pathogenesis.

Main Methods:

• X-ray crystallography was used to determine the 2.8-Å structure of the human p300 catalytic core.
• Analysis of domain interactions and the impact of disease-associated mutations.

Main Results:

• The structure reveals an assembled configuration of the bromodomain, CH2, PHD, RING, and HAT domains.
• The RING domain is positioned over the HAT substrate-binding pocket, suggesting a regulatory role.
• Disease mutations affecting RING domain attachment lead to increased HAT activity, indicating its inhibitory function.

Conclusions:

• The p300 structure provides insights into the coupling of chromatin targeting and HAT regulation.
• The inhibitory role of the RING domain is uncovered, explaining how its disruption leads to dysregulation and disease.