Dynamics of the histone acetyltransferase lysine-rich loop in the catalytic core of the CREB-binding protein

TitleDynamics of the histone acetyltransferase lysine-rich loop in the catalytic core of the CREB-binding protein
Publication TypeJournal Article
Year of Publication2022
AuthorsSalutari I., Caflisch A.
JournalJournal of Chemical Information and Modeling
Volume62
Issue4
Pagination1014–1024
Date Published2022 Feb 04
Type of ArticleResearch Article
Abstract

The tight control of transcriptional coactivators is a fundamental aspect of gene expression in cells. The regulation of the CREB-binding protein (CBP) and p300 coactivators, two paralog multidomain proteins, involves an autoinhibitory loop (AIL) of the histone acetyltransferase (HAT) domain. There is experimental evidence for the AIL engaging with the HAT binding site, thus interrupting the acetylation of histone tails or other proteins. Both CBP and p300 contain a domain of about 110 residues (called the bromodomain) that recognizes histone tails with one or more acetylated lysine side chains. Here, we investigate by molecular dynamics simulations whether the AIL of CBP (residues 1556-1618) acetylated at the side chain of Lys1595 can bind to the bromodomain. The structural instability and fast unbinding kinetics of the AIL from the bromodomain pocket suggest that the AIL is not a ligand of the bromodomain on the same protein chain. This is further supported by the absence of strong and persistent contacts at the binding interface. Furthermore, the simulations of unbinding show an initial fast detachment of the acetylated lysine and a slower phase necessary for complete AIL dissociation. We provide further evidence for the instability of the AIL intramolecular binding by comparison with a natural ligand, the histone peptide H3K56ac, which shows higher stability in the pocket.

DOI10.1021/acs.jcim.1c01423
pubindex

0274

Alternate JournalJ. Chem. Inf. Model.
PubMed ID35119862