KIX domain

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KIX (CBP)
KIX and TAD in complex, structure by Lecoq 2017, PDB 5U4K.jpg
Complex between the KIX domain of CBP (yellow, green and cyan) and the C-terminal transactivation domain of p65/RELA (red) [1]
Identifiers
SymbolKIX
Pfam PF02172
Pfam clan CL0589
InterPro IPR003101
CATH 1sb0
SCOP2 1sb0 / SCOPe / SUPFAM
KIX (MED15)
Identifiers
SymbolKIX_2
Pfam PF16987
InterPro IPR036546

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.

Contents

The KIX domain was originally discovered in 1996 as the specific and minimal region in CBP that binds and interacts with phosphorylated CREB to activate transcription. [2] It was thus first termed CREB-binding domain. However, when it was later discovered that it also binds many other proteins, the more general name KIX domain became favoured. The KIX domain contains two separate binding sites: the "c-Myb site", named after the oncoprotein c-Myb, and the "MLL site", named after the proto-oncogene MLL (Mixed Lineage Leukemia, KMT2A). [3]

The paralogous coactivators CBP (CREBBP) and P300 (EP300) are recruited to DNA-bound transcription factors to activate transcription. Coactivators can associate with promoters and enhancers in the DNA only indirectly through protein-protein contacts with transcription factors. CBP and P300 activate transcription synergistically in two ways: first, by remodelling and relaxing chromatin through their intrinsic histone acetyltransferase activity, and second, by recruiting the basal transcription machinery, such as RNA polymerase II. [4]

The KIX domain belongs to the proposed GACKIX domain superfamily. GACKIX comprises structurally and functionally highly homologous domains in related proteins. It is named after the protein GAL11 / ARC105 (MED15), the plant protein CBP-like, and the KIX domain from CBP and P300. [5] Additional instances include RECQL5 and related plant proteins. [6] [7] All of these contain a KIX domain or KIX-related domain that interacts with the transactivation domain of many different transcription factors. The distinction between a KIX domain, a KIX-related domain and a GACKIX domain is subject to an ongoing debate and not clearly defined.

The full CBP/P300 protein

Overview of the structural domains of CBP Structure CREBBP de.svg
Overview of the structural domains of CBP

Aside from the KIX domain, CBP and P300 contain many other protein binding domains that should not be confused (numbers are aa numberings):

All three CH (cysteine/histidine-rich) domains are zinc fingers. [9]

Interactions

9aaTAD-KIX domain complexes Piskacek Figures v9b.jpg
9aaTAD-KIX domain complexes

Human and animal proteins:

Yeast proteins:

Viral proteins:

Related Research Articles

Histone acetyltransferase Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

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.

EP300 Protein-coding gene in the species Homo sapiens

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.

Coactivator (genetics)

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

p300-CBP coactivator family

The p300-CBP coactivator family in humans is composed of two closely related transcriptional co-activating proteins :

  1. p300
  2. CBP

In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that repress are known as corepressors. The mechanism of action of transcription coregulators is to modify chromatin structure and thereby make the associated DNA more or less accessible to transcription. In humans several dozen to several hundred coregulators are known, depending on the level of confidence with which the characterisation of a protein as a coregulator can be made. One class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.

PCAF

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 Nuclear protein that binds to CREB

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 CREB domains: the nuclear receptor interaction domain (RID), the KIX domain, the cysteine/histidine regions and the interferon response binding domain (IBiD). The CREB protein domains, KIX, TAZ1 and TAZ2, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.

TCF3

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.

CREB1

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.

FOXO3 Protein-coding gene in the species Homo sapiens

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.

KMT2A Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase 2A also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX) is an enzyme that in humans is encoded by the KMT2A gene.

FOXO4 Protein

Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.

CITED2

Cbp/p300-interacting transactivator 2 is a protein that in humans is encoded by the CITED2 gene.

CITED1

Cbp/p300-interacting transactivator 1 is a protein that in humans is encoded by the CITED1 gene.

CRTC2

CREB regulated transcription coactivator 2, also known as CRTC2, is a protein which in humans is encoded by the CRTC2 gene.

Forkhead box protein O1 Protein

Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

TAZ zinc finger

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 molecular biology the ZZ-type zinc finger domain is a type of protein domain that was named because of its ability to bind two zinc ions. These domains contain 4-6 Cys residues that participate in zinc binding, including a Cys-X2-Cys motif found in other zinc finger domains. These zinc fingers are thought to be involved in protein-protein interactions. The structure of the ZZ domain shows that it belongs to the family of cross-brace zinc finger motifs that include the PHD, RING, and FYVE domains. ZZ-type zinc finger domains are found in:

Deficiency of RbAp48 protein and memory loss

Memory is commonly referred to as the ability to encode, store, retain and subsequently recall information and past experiences in the human brain. This process involves many proteins, one of which is the Histone-binding protein RbAp48, encoded by the RBBP4 gene in humans.

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). 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.

References

  1. 1 2 Lecoq L, Raiola L, Chabot PR, Cyr N, Arseneault G, Legault P, Omichinski JG (May 2017). "Structural characterization of interactions between transactivation domain 1 of the p65 subunit of NF-κB and transcription regulatory factors". Nucleic Acids Research. 45 (9): 5564–5576. doi:10.1093/nar/gkx146. PMC   5435986 . PMID   28334776.
  2. ↑ Parker D, Ferreri K, Nakajima T, LaMorte VJ, Evans R, Koerber SC, et al. (February 1996). "Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism". Molecular and Cellular Biology. 16 (2): 694–703. doi:10.1128/MCB.16.2.694. PMC   231049 . PMID   8552098.
  3. ↑ Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE (November 2002). "Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain". The Journal of Biological Chemistry. 277 (45): 43168–74. doi: 10.1074/jbc.M207660200 . PMID   12205094.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Thakur JK, Yadav A, Yadav G (February 2014). "Molecular recognition by the KIX domain and its role in gene regulation". Nucleic Acids Research. 42 (4): 2112–25. doi:10.1093/nar/gkt1147. PMC   3936767 . PMID   24253305.
  5. ↑ Novatchkova M, Eisenhaber F (January 2004). "Linking transcriptional mediators via the GACKIX domain super family". Current Biology. 14 (2): R54-5. doi: 10.1016/j.cub.2003.12.042 . PMID   14738747.
  6. ↑ Popuri V, Ramamoorthy M, Tadokoro T, Singh DK, Karmakar P, Croteau DL, Bohr VA (July 2012). "Recruitment and retention dynamics of RECQL5 at DNA double strand break sites". DNA Repair. 11 (7): 624–35. doi:10.1016/j.dnarep.2012.05.001. PMC   3374033 . PMID   22633600.
  7. ↑ Yadav A, Thakur JK, Yadav G (November 2017). "KIXBASE: A comprehensive web resource for identification and exploration of KIX domains". Scientific Reports. 7 (1): 14924. Bibcode:2017NatSR...714924Y. doi:10.1038/s41598-017-14617-0. PMC   5668377 . PMID   29097748.
  8. 1 2 3 4 5 6 UniProt and InterPro entry for CBP ( Q92793 ) and P300 ( Q09472 )
  9. 1 2 Park S, Martinez-Yamout MA, Dyson HJ, Wright PE (August 2013). "The CH2 domain of CBP/p300 is a novel zinc finger". FEBS Letters. 587 (16): 2506–11. doi:10.1016/j.febslet.2013.06.051. PMC   3765250 . PMID   23831576.
  10. 1 2 Lin CH, Hare BJ, Wagner G, Harrison SC, Maniatis T, Fraenkel E (September 2001). "A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies". Molecular Cell. 8 (3): 581–90. doi: 10.1016/S1097-2765(01)00333-1 . PMID   11583620.
  11. ↑ Demarest SJ, Deechongkit S, Dyson HJ, Evans RM, Wright PE (January 2004). "Packing, specificity, and mutability at the binding interface between the p160 coactivator and CREB-binding protein". Protein Science. 13 (1): 203–10. doi:10.1110/ps.03366504. PMC   2286511 . PMID   14691235.
  12. ↑ Sheppard HM, Harries JC, Hussain S, Bevan C, Heery DM (January 2001). "Analysis of the steroid receptor coactivator 1 (SRC1)-CREB binding protein interaction interface and its importance for the function of SRC1". Molecular and Cellular Biology. 21 (1): 39–50. doi:10.1128/MCB.21.1.39-50.2001. PMC   86566 . PMID   11113179.
  13. ↑ Takahata S, Ozaki T, Mimura J, Kikuchi Y, Sogawa K, Fujii-Kuriyama Y (September 2000). "Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3". Genes to Cells. 5 (9): 739–47. doi:10.1046/j.1365-2443.2000.00363.x. PMID   10971655. S2CID   41625860.
  14. ↑ Xu H, Gustafson CL, Sammons PJ, Khan SK, Parsley NC, Ramanathan C, et al. (June 2015). "Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus". Nature Structural & Molecular Biology. 22 (6): 476–484. doi:10.1038/nsmb.3018. PMC   4456216 . PMID   25961797.
  15. 1 2 3 4 5 6 7 8 9 10 11 12 13 Vo N, Goodman RH (April 2001). "CREB-binding protein and p300 in transcriptional regulation". The Journal of Biological Chemistry. 276 (17): 13505–8. doi: 10.1074/jbc.R000025200 . PMID   11279224.
  16. ↑ Wang F, Marshall CB, Li GY, Yamamoto K, Mak TW, Ikura M (December 2009). "Synergistic interplay between promoter recognition and CBP/p300 coactivator recruitment by FOXO3a". ACS Chemical Biology. 4 (12): 1017–27. doi:10.1021/cb900190u. PMID   19821614.
  17. ↑ Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S (March 1999). "Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3". The Journal of Biological Chemistry. 274 (12): 8143–52. doi: 10.1074/jbc.274.12.8143 . PMID   10075717.
  18. ↑ Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ (April 2001). "MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein". Molecular and Cellular Biology. 21 (7): 2249–58. doi:10.1128/MCB.21.7.2249-2258.2001. PMC   86859 . PMID   11259575.
  19. ↑ Gerritsen ME, Williams AJ, Neish AS, Moore S, Shi Y, Collins T (April 1997). "CREB-binding protein/p300 are transcriptional coactivators of p65". Proceedings of the National Academy of Sciences of the United States of America. 94 (7): 2927–32. Bibcode:1997PNAS...94.2927G. doi: 10.1073/pnas.94.7.2927 . PMC   20299 . PMID   9096323.
  20. ↑ Bradney C, Hjelmeland M, Komatsu Y, Yoshida M, Yao TP, Zhuang Y (January 2003). "Regulation of E2A activities by histone acetyltransferases in B lymphocyte development". The Journal of Biological Chemistry. 278 (4): 2370–6. doi: 10.1074/jbc.M211464200 . PMID   12435739.
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