Summary: KIX domain
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KIX domain Edit Wikipedia article
|SCOP2||1sb0 / SCOPe / SUPFAM|
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 Î±-helices and two short 310-helices.
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. 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).
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.
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. Additional instances include RECQL5 and related plant proteins. 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
Aside from the KIX domain, CBP and P300 contain many other protein binding domains that should not be confused (numbers are aa numberings):
- CH1/TAZ1 domain, CBP[347â€“433], P300[323-423]
- KIX domain, CBP[587â€“666], P300[566â€“645]
- Bromodomain, CBP[1103â€“1175], P300[1067â€“1139]
- CH2 domain (IPR010303), CBP[1191â€“1317], P300[1155-1280].
- HAT domain, CBP[1323â€“1700], P300[1287â€“1663]
- CH3/ZZ domain, CBP[1701-1744], P300[1664-1707]
- CH3/TAZ2 domain, CBP[1765â€“1846], P300[1728-1809]
- IRF-3 binding (i-BiD), nuclear receptor coactivator binding (NCBD), or SRC1 interaction domain (SID; IPR014744), CBP[2020-2113], P300[1992-2098].
Human and animal proteins:
- ARNTL (BMAL1)
- ATF4 (CREB2)
- Cubitus interruptus (in D. melanogaster)
- ELK4 (SAP1)
- FOXO3 (FOXO3a)
- JUN (c-Jun)
- KMT2A (MLL)
- MYB (c-Myb)
- NFE2 (NF-E2 p45)
- RELA (NF-ÎºB p65)
- TCF3 (E2A)
- TP53 (p53)
- 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-ÎºB and transcription regulatory factors". Nucleic Acids Research. 45 (9): 5564â€“5576. doi:10.1093/nar/gkx146. PMCÂ 5435986. PMIDÂ 28334776.
- Parker D, Ferreri K, Nakajima T, LaMorte VJ, Evans R, Koerber SC, etÂ 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): 694â€“703. doi:10.1128/MCB.16.2.694. PMCÂ 231049. PMIDÂ 8552098.
- 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): 43168â€“74. doi:10.1074/jbc.M207660200. PMIDÂ 12205094.
- 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): 2112â€“25. doi:10.1093/nar/gkt1147. PMCÂ 3936767. PMIDÂ 24253305.
- 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. PMIDÂ 14738747.
- 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): 624â€“35. doi:10.1016/j.dnarep.2012.05.001. PMCÂ 3374033. PMIDÂ 22633600.
- 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. PMCÂ 5668377. PMIDÂ 29097748.
- UniProt and InterPro entry for CBP ( ) and P300 ( )
- 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): 2506â€“11. doi:10.1016/j.febslet.2013.06.051. PMCÂ 3765250. PMIDÂ 23831576.
- 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): 581â€“90. doi:10.1016/S1097-2765(01)00333-1. PMIDÂ 11583620.
- 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): 203â€“10. doi:10.1110/ps.03366504. PMCÂ 2286511. PMIDÂ 14691235.
- 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): 39â€“50. doi:10.1128/MCB.21.1.39-50.2001. PMCÂ 86566. PMIDÂ 11113179.
- 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): 739â€“47. doi:10.1046/j.1365-2443.2000.00363.x. PMIDÂ 10971655. S2CIDÂ 41625860.
- Xu H, Gustafson CL, Sammons PJ, Khan SK, Parsley NC, Ramanathan C, etÂ al. (June 2015). "Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus". Nature Structural & Molecular Biology. 22 (6): 476â€“484. doi:10.1038/nsmb.3018. PMCÂ 4456216. PMIDÂ 25961797.
- Vo N, Goodman RH (April 2001). "CREB-binding protein and p300 in transcriptional regulation". The Journal of Biological Chemistry. 276 (17): 13505â€“8. doi:10.1074/jbc.R000025200. PMIDÂ 11279224.
- 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): 1017â€“27. doi:10.1021/cb900190u. PMIDÂ 19821614.
- 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): 8143â€“52. doi:10.1074/jbc.274.12.8143. PMIDÂ 10075717.
- 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): 2249â€“58. doi:10.1128/MCB.21.7.2249-2258.2001. PMCÂ 86859. PMIDÂ 11259575.
- 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): 2927â€“32. Bibcode:1997PNAS...94.2927G. doi:10.1073/pnas.94.7.2927. PMCÂ 20299. PMIDÂ 9096323.
- 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): 2370â€“6. doi:10.1074/jbc.M211464200. PMIDÂ 12435739.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
KIX domain Provide feedback
This KIX domain is an activator-binding domain .
Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Naar AM;, Nature. 2008;452:604-609.: A nuclear receptor-like pathway regulating multidrug resistance in fungi. PUBMED:18385733 EPMC:18385733
Internal database links
|Similarity to PfamA using HHSearch:||KIX Med15|
This tab holds annotation information from the InterPro database.
InterPro entry IPR036546
GAL11 is a component of the Mediator complex, a co-activator that plays critical roles in transcriptional activation. The GAL11/MED15 subunit has an N-terminal KIX domain, which is an activator-binding domain. This domain contains a docking site for the activation domain of yeast drug resistance protein Pdr1, therefore is thought to be involved in antifungal/xenobiotic-dependent regulation of multidrug resistance [ PUBMED:18385733 ].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
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Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
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This superfamily is characterised by structures with three helices in a partly opened bundle bundle. There are both creb-binding proteins and activator-binding proteins on mediator subunits, such as higher eukaryotic 13 and fungal 15.
The clan contains the following 2 members:KIX KIX_2
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||59|
|Number in full:||1939|
|Average length of the domain:||77.80 aa|
|Average identity of full alignment:||35 %|
|Average coverage of the sequence by the domain:||10.72 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||8|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the KIX_2 domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.