P300-CBP coactivator family

Protein family

The p300 CBP coactivator family in humans is composed of two closely related transcriptional co activating proteins (or coactivators):

p300 (also called EP300 or E1A binding protein p300)
CBP (also known as CREB binding protein or CREBBP)

Both p300 and CBP interact with numerous transcription factors and act to increase the expression of their target genes.

p300 and CBP have similar structures. Both contain five protein interaction domains: the nuclear receptor interaction domain (RID), the KIX domain (CREB and MYB interaction domain), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to
a sequence spanning both transactivation domains 9aaTADs of transcription factor p53. In addition p300 and CBP each contain a protein or histone acetyltransferase (PAT/HAT) domain and a bromodomain that binds acetylated lysines and a PHD finger motif with unknown function. The conserved domains are connected by long stretches of unstructured linkers.

An example of a process involving p300 and CBP is G protein signaling. Some G proteins stimulate adenylate cyclase that results in elevation of cAMP. cAMP stimulates PKA, which consists of four subunits, two regulatory and two catalytic. Binding of cAMP to the regulatory subunits causes release of the catalytic subunits. These subunits can then enter the nucleus to interact with transcriptional factors, thus affecting gene transcription. The transcription factor CREB, which interacts with a DNA sequence called a cAMP response element (or CRE), is phosphorylated on a serine (Ser 133) in the KID domain. This modification is PKA mediated, and promotes the interaction of the KID domain of CREB with the KIX domain of CBP or p300 and enhances transcription of CREB target genes, including genes that aid gluconeogenesis. This pathway can be initiated by adrenaline activating β adrenergic receptors on the cell surface.

Mutations in CBP, and to a lesser extent p300, are the cause of Rubinstein Taybi Syndrome, which is characterized by severe mental retardation. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of CBP or p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the CBP or p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of CBP or p300 protein leads to the specific features of Rubinstein Taybi syndrome, it is clear that the loss of one copy of the CBP or p300 gene disrupts normal development. Defects in CBP HAT activity appears to cause problems in long term memory formation. CBP and p300 have also been found to be involved in multiple rare chromosomal translocations that are associated with acute myeloid leukemia. In addition, mice which lack one functional copy (allele) of both the CBP and p300 genes (i. e. are heterozygous for both CBP and p300) and thus have half of the normal amount of both CBP and p300, also die early in embryogenesis. Together, the data indicate that, while individual cell types require different amounts of CBP and p300 to develop or survive and some cell types are more tolerant of loss of CBP or p300 than the whole organism, it appears that many, if not all cell types may require at least some p300 or CBP to develop.