Structural and Functional Characterization of CREB-Binding Protein (CREBBP) as a Histone Propionyltransferase

Authors

Guiling Cui
Marie Ley
Ariel E Mechaly
Linh-Chi Bui
Christina Michail
Jérémy Berthelet
Julien Dairou
Haopeng Yang
Guillaume Chevreux
Gautier Moroy
Michael R Green
Ahmed Haouz
Fernando Rodrigues Lima

Publication Date

7-2-2025

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2025.110444

PMID

40615044

PMCID

PMC12305233

PubMedCentral® Posted Date

7-2-2025

PubMedCentral® Full Text Version

Post-print

Abstract

In addition to histone acetylation, histone lysine propionylation (such as the H3K18Pr mark) has recently attracted significant attention as a common and abundant modification linking the cellular metabolic state and gene expression. CREB-binding protein (CREBBP) and EP300 are key histone acetyltransferases that play a critical role in gene expression through their catalytic activity. Although CREBBP and EP300 are homologous enzymes with high structural similarities, they exhibit both redundant and specific functions. Dissecting the shared and divergent properties of CREBBP and EP300 is thus important to understand their roles. However, despite the importance of CREBBP, most mechanistic and structural studies have focused on EP300, leaving much less information about CREBBP. Interestingly, recent enzymatic and structural studies have demonstrated that EP300 can also function as a histone propionyltransferase. Using a combination of acyltransferase assays with different acyl-CoA cofactors and with peptides, recombinant histone, or recombinant nucleosomes as substrates, we provide enzymatic evidence that, in addition to its well-documented acetyltransferase activity, CREBBP readily propionylates histone H3 in vitro, notably generating the H3K18Pr mark. Importantly, subsequent cellular studies using CRISPR-Cas9-edited cells further support that CREBBP can act as a histone propionyltransferase in vivo, notably depositing the H3K18Pr mark. Finally, the crystal structures of the human CREBBP histone acetyltransferase domain in complex with propionyl-CoA or in complex with Lys-CoA provide the structural basis for the histone propionyltransferase properties of CREBBP. Taken together, these findings provide new insights into the enzymatic functions of CREBBP and a better understanding of the mechanisms linking cellular metabolism and epigenetic regulation.

Keywords

lysine propionylation, acetyltransferase, protein acylation, propionyl-CoA, crystal structure, CRISPR–Cas9, CREBBP

Published Open-Access

yes

Recommended Citation

Cui, Guiling; Ley, Marie; Mechaly, Ariel E; et al., "Structural and Functional Characterization of CREB-Binding Protein (CREBBP) as a Histone Propionyltransferase" (2025). Faculty, Staff and Student Publications. 4458.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4458