Dynamics of the Histone Acetyltransferase Lysine-Rich Loop in the Catalytic Core of the CREB-Binding Protein

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.

Unlocking phenotypic plasticity provides novel insights for immunity and personalized therapy in lung adenocarcinoma

“…Studies have found that the most distinct group of protein modifiers is histone acetyltransferase (HATS). Most groups of histone acetylationase have substrate specificity to guide the acetylation of a particular residue within one or more core groups (Salutari et al, 2022). However, these substrate specificities are not fixed and can be changed by Frontiers in Genetics frontiersin.org catalytic subunits and protein complexes.…”

Loop Dynamics and Conformational Flexibility in Dengue Serine Protease Activity: Noninvasive Perturbation by Solvent Exchange

“…7−13 It is recognized that such important loops/residues have certain kinds of conformations/motions that are absolutely imperative for enzyme kinetics. 14,15 An example is the WPD (Trp−Pro−Asp) loop of several protein tyrosine phosphatases (PTP). According to the research of Crean et al, WPD along with the neighboring loop dynamics regulates the catalytic activity of the PTPs and responds differently to environmental changes.…”

“…Because of the biological significance of DENV NS2B/NS3 serine protease, continuous effort is being given to develop a suitable drug against it. However, to develop an effective drug candidate, it is necessary to understand the intricacy of the protein machinery. , Key intramolecular loops or residues are known to regulate the activation or inactivation status of several enzymes. − It is recognized that such important loops/residues have certain kinds of conformations/motions that are absolutely imperative for enzyme kinetics. , An example is the WPD (Trp–Pro–Asp) loop of several protein tyrosine phosphatases (PTP). According to the research of Crean et al, WPD along with the neighboring loop dynamics regulates the catalytic activity of the PTPs and responds differently to environmental changes .…”