CREB-binding protein (CBP) histone acetyltransferase (HAT) domain (CBP HAT domain)

The CREB-binding protein (CBP) histone acetyltransferase (HAT) domain is the catalytic core of the CBP protein, a ubiquitous transcriptional coactivator that plays a central role in epigenetic regulation [1, 2]. It functions by transferring acetyl groups from acetyl-CoA to lysine residues on histones, specifically H3K18 and H3K27, as well as non-histone proteins like p53 and MYC [3, 4]. This acetylation neutralizes the positive charge of histones, leading to a more relaxed chromatin structure that facilitates the binding of the transcriptional machinery and promotes gene expression [1, 5]. Beyond its catalytic role, the HAT domain acts as a scaffold for various transcription factors, integrating multiple signaling pathways essential for embryonic development and cell cycle progression [2, 5]. Dysregulation of the CBP HAT domain is a hallmark of several diseases, most notably in cancers such as acute myeloid leukemia and prostate cancer, where it drives oncogenic gene expression programs [5, 6]. Conversely, loss-of-function mutations in this domain are the primary cause of Rubinstein-Taybi syndrome, a condition characterized by developmental delays and physical abnormalities [2, 5]. Therapeutic targeting of the HAT domain has led to the development of small-molecule inhibitors such as A-485 and CPI-1612, which competitively block the acetyl-CoA binding site to suppress tumor growth [6, 7]. Ongoing research also explores the use of HAT activators, such as TTK21, to potentially restore cognitive function in neurodegenerative conditions, highlighting the domain's diverse therapeutic potential [8, 9].

Other names

CREBBPKAT3ARSTSRSTS1CBPHistone lysine acetyltransferase CREBBP

Competitive inhibition of the acetyl-CoA binding site within the histone acetyltransferase domain, preventing the catalytic transfer of acetyl groups to lysine residues on histones and non-histone substrates.