The transactivation domain or trans-activating domain (TAD) is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activation functions (AFs). [1] TADs are named after their amino acid composition. These amino acids are either essential for the activity or simply the most abundant in the TAD. Transactivation by the Gal4 transcription factor is mediated by acidic amino acids, whereas hydrophobic residues in Gcn4 play a similar role. Hence, the TADs in Gal4 and Gcn4 are referred to as acidic or hydrophobic, respectively. [2] [3] [4] [5] [6] [7] [8] [9]
In general we can distinguish four classes of TADs: [10]
Alternatively, since similar amino acid compositions does not necessary mean similar activation pathways, TADs can be grouped by the process they stimulate, either initiation or elongation. [15]
Nine-amino-acid transactivation domain (9aaTAD) defines a domain common to a large superfamily of eukaryotic transcription factors represented by Gal4, Oaf1, Leu3, Rtg3, Pho4, Gln3, Gcn4 in yeast, and by p53, NFAT, NF-κB and VP16 in mammals. The definition largely overlaps with an "acidic" family definition. A 9aaTAD prediction tool is available. [16] 9aaTADs tend to have an associated 3-aa hydrophobic (usually Leu-rich) region immediately to its N-terminal. [17]
9aaTAD transcription factors p53, VP16, MLL, E2A, HSF1, NF-IL6, NFAT1 and NF-κB interact directly with the general coactivators TAF9 and CBP/p300. [16] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] p53 9aaTADs interact with TAF9, GCN5 and with multiple domains of CBP/p300 (KIX, TAZ1,TAZ2 and IBiD). [30] [31] [32] [33] [34]
The KIX domain of general coactivators Med15(Gal11) interacts with 9aaTAD transcription factors Gal4, Pdr1, Oaf1, Gcn4, VP16, Pho4, Msn2, Ino2 and P201. Positions 1, 3-4, and 7 of the 9aaTAD are the main residues that interact with KIX. [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] Interactions of Gal4, Pdr1 and Gcn4 with Taf9 have been observed. [8] [51] [52] 9aaTAD is a common transactivation domain which recruits multiple general coactivators TAF9, MED15, CBP/p300 and GCN5. [16]
Source | 9aaTAD | Peptide-KIX interaction (NMR) |
---|---|---|
p53 TAD1 | E TFSD LWKL | LSPEETFSDLWKLPE |
p53 TAD2 | D DIEQ WFTE | QAMDDLMLSPDDIEQWFTEDPGPD |
MLL | S DIMD FVLK | DCGNILPSDIMDFVLKNTP |
E2A | D LLDF SMMF | PVGTDKELSDLLDFSMMFPLPVT |
Rtg3 | E TLDF SLVT | E2A homolog |
CREB | R KILN DLSS | RREILSRRPSYRKILNDLSSDAP |
CREBaB6 | E AILA ELKK | CREB-mutant binding to KIX |
Gli3 | D DVVQ YLNS | TAD homology to CREB/KIX |
Gal4 | D DVYN YLFD | Pdr1 and Oaf1 homolog |
Oaf1 | D LFDY DFLV | DLFDYDFLV |
Pip2 | D FFDY DLLF | Oafl homolog |
Pdr1 | E DLYS ILWS | EDLYSILWSDWY |
Pdr3 | T DLYH TLWN | Pdr1 homolog |
Glutamine (Q)-rich TADs are found in POU2F1 (Oct1), POU2F2 (Oct2), and Sp1 (see also Sp/KLF family). [12] Although such is not the case for every Q-rich TAD, Sp1 is shown to interact with TAF4 (TAFII 130), a part of the TFIID assembly. [15] [53]
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.
Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene. It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling by allowing histone proteins to wrap DNA less tightly. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.
The p300-CBP coactivator family in humans is composed of two closely related transcriptional co-activating proteins :
P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.
CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.
The nuclear receptor coactivator 1 (NCOA1), also called steroid receptor coactivator-1 (SRC-1), is a transcriptional coregulatory protein that contains several nuclear receptor–interacting domains and possesses intrinsic histone acetyltransferase activity. It is encoded by the gene NCOA1.
Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene.
Transcription factor 3, also known as TCF3, is a protein that in humans is encoded by the TCF3 gene. TCF3 has been shown to directly enhance Hes1 expression.
CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. The binding of CREB1 stimulates transcription.
Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the MED1 gene. MED1 functions as a nuclear receptor coactivator.
Host cell factor 1, also known as VP16-accessory protein, is a protein that in humans is encoded by the HCFC1 gene.
TAF9 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 32kDa, also known as TAF9, is a protein that in humans is encoded by the TAF9 gene.
Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.
Transcriptional adapter 3-like is a protein that in humans is encoded by the TADA3 gene. Cytogenetic location: 3p25.3
Mediator of RNA polymerase II transcription subunit 15, also known as Gal11, Spt13 in yeast and PCQAP, ARC105, or TIG-1 in humans is a protein encoded by the MED15 gene.
Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of coregulators for nuclear receptors and other transcription factors was previously maintained at the Nuclear Receptor Signaling Atlas website which has since been replaced by the Signaling Pathways Project website.
In molecular biology, TAZ zinc finger domains are zinc-containing domains found in the homologous transcriptional co-activators CREB-binding protein (CBP) and the P300. CBP and P300 are histone acetyltransferases that catalyse the reversible acetylation of all four histones in nucleosomes, acting to regulate transcription via chromatin remodelling. These large nuclear proteins interact with numerous transcription factors and viral oncoproteins, including p53 tumour suppressor protein, E1A oncoprotein, MyoD, and GATA-1, and are involved in cell growth, differentiation and apoptosis. Both CBP and P300 have two copies of the TAZ domain, one in the N-terminal region, the other in the C-terminal region. The TAZ1 domain of CBP and P300 forms a complex with CITED2, inhibiting the activity of the hypoxia inducible factor (HIF-1alpha) and thereby attenuating the cellular response to low tissue oxygen concentration. Adaptation to hypoxia is mediated by transactivation of hypoxia-responsive genes by hypoxia-inducible factor-1 (HIF-1) in complex with the CBP and p300 transcriptional coactivators.
In biochemistry, the KIX domain (kinase-inducible domain (KID) interacting domain) or CREB binding domain is a protein domain of the eukaryotic transcriptional coactivators CBP and P300. It serves as a docking site for the formation of heterodimers between the coactivator and specific transcription factors. Structurally, the KIX domain is a globular domain consisting of three α-helices and two short 310-helices.
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