P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 and trancriptional coactivator

Coactivator (genetics)

A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....

 associated with p53

P53

p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

.

Structure

Several domains of PCAF can act independently or in unison to enable its functions. PCAF has separate acetyltransferase

Acetyltransferase

Acetyltransferase is a type of transferase enzyme that transfers an acetyl group.Examples include:* Histone acetyltransferases including CBP histone acetyltransferase* Choline acetyltransferase* Chloramphenicol acetyltransferase...

 and E3 ubiquitin ligase domains as well as a bromodomain

Bromodomain

A bromodomain is a protein domain that recognizes acetylated lysine residues such as those on the N-terminal tails of histones. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha...

 for interaction with other proteins. PCAF also possesses sites for its own acetylation and ubiquitination.

Function

CBP and p300

EP300

E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...

 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun

C-jun

c-Jun is the name of a gene and protein that, in combination with c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the c-jun gene. It is activated through double phosphorylation by the...

 and the adenoviral oncoprotein E1A. The protein encoded by the PCAF gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histone

Histone

In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...

s and nucleosome

Nucleosome

Nucleosomes are the basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound around a histone protein core. This structure is often compared to thread wrapped around a spool....

 core particles, indicating that this protein plays a direct role in transcriptional regulation.

Regulation

The acetyltransferase

Acetyltransferase

Acetyltransferase is a type of transferase enzyme that transfers an acetyl group.Examples include:* Histone acetyltransferases including CBP histone acetyltransferase* Choline acetyltransferase* Chloramphenicol acetyltransferase...

 activity and cellular location of PCAF are regulated through acetylation of PCAF itself. PCAF may be autoacetylated (acetylated by itself) or by p300

EP300

E1A binding protein p300 also known as EP300 or p300 is a protein that, in humans, is encoded by the EP300 gene. This protein regulates the activity of many genes in tissues throughout the body...

. Acetylation leads to migration to the nucleus and enhances its acetyltransferase activity. PCAF interacts with and is deacetylated by HDAC3

HDAC3

Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,...

, leading to a reduction in PCAF acetyltransferase activity and cytoplasmic localisation.

Protein interactions

PCAF forms complexes with numerous proteins that guide its activity. For example PCAF is recruited by ATF

Activating transcription factor

In molecular biology, activating transcription factor, ATF, is a class of AP-1 transcription factor dimers.Genes include ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7....

 to acetylate histone

Histone

In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...

s and promote transcription of ATF4 target genes.

Targets

There are various protein targets of PCAF's acetyltransferase activity including transcription factors such as Fli1

FLI1

Friend leukemia integration 1 transcription factor , also known as proto-oncogene Fli-1 or transcription factor ERGB, is a protein that in humans is encoded by the human FLI1 gene. - Function :...

, p53 and numerous histone residues.
Hdm2, itself a ubiquitin ligase that targets p53, has also been demonstrated to be a target of the ubiquitin-ligase activity of PCAF.

Interactions

PCAF has been shown to interact

Protein-protein interaction

Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with Beta-catenin

Beta-catenin

Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...

, Twist transcription factor

Twist transcription factor

Twist transcription factor is a basic-helix-loop-helix transcription factor associated with Saethre-Chotzen syndrome.-Interactions:Twist transcription factor has been shown to interact with EP300, TCF3 and PCAF.-External links:*...

, Myc

Myc

Myc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...

, IRF1

IRF1

Interferon regulatory factor 1 is a protein that in humans is encoded by the IRF1 gene.- Function :Interferon regulatory factor 1 was the first member of the interferon regulatory transcription factor family identified...

, IRF2

IRF2

Interferon regulatory factor 2 is a protein that in humans is encoded by the IRF2 gene.-Interactions:IRF2 has been shown to interact with BRD7, EP300 and PCAF.-Further reading:- External links :...

, Transformation/transcription domain-associated protein

Transformation/transcription domain-associated protein

Transformation/transcription domain-associated protein, also known asTRRAP, is a protein that in humans is encoded by the TRRAP gene. TRRAP belongs to the phosphatidylinositol 3-kinase-related kinase protein family.- Function :...

, CREB binding protein

CREB binding protein

CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBP gene.The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor...

, BRCA2

BRCA2

BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....

, KLF13

KLF13

Kruppel-like factor 13, also known as KLF13, is a protein that in humans is encoded by the KLF13 gene.- Function :KLF13 belongs to a family of transcription factors that contain 3 classical zinc finger DNA-binding domains consisting of a zinc atom tetrahedrally coordinated by 2 cysteines and 2...

, TCF3

TCF3

Transcription factor 3 , also known as TCF3, is a protein that in humans is encoded by the TCF3 gene...

, RBPJ

RBPJ

Recombining binding protein suppressor of hairless is a protein that in humans is encoded by the RBPJ gene.RBPJ, also named as CBF1, is a human homolog for the Drosophila gene Suppressor of Hairless...

, POLR2A

POLR2A

DNA-directed RNA polymerase II subunit RPB1 is an enzyme that in humans is encoded by the POLR2A gene.-Interactions:POLR2A has been shown to interact with Transcription elongation regulator 1, CREB-binding protein, BRCA1, GTF2H4, TATA-binding protein, PCAF, GTF2F1, SUPT5H, Transcription Factor II...

, Nuclear receptor coactivator 1

Nuclear receptor coactivator 1

The nuclear receptor coactivator 1 is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity . NCOA1 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA1, in turn, acylates...

, EVI1

EVI1

MDS1 and EVI1 complex locus protein EVI1 also known as ecotropic virus integration site 1 protein homolog or positive regulatory domain zinc finger protein 3 is a protein that in humans is encoded by the MECOM gene. EVI1 was first identified as a common retroviral integration site in AKXD murine...

, Mdm2

Mdm2

Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...

 and HNF1A

HNF1A

HNF1 homeobox A , also known as HNF1A, is a human gene.The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes.-Interactions:HNF1A has been shown to interact with PCAF, Src,...

.

Further reading