KIX domain explained

Symbol:	KIX
KIX (CBP)
Pfam:	PF02172
Pfam Clan:	CL0589
Interpro:	IPR003101
Scop:	1sb0
Cath:	1sb0

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.

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.^[1] 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).^[2]

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.^[3]

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.^[4] Additional instances include RECQL5 and related plant proteins.^{[5] [6]} 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[347–433], P300[323-423]^[7]
• KIX domain, CBP[587–666], P300[566–645]^[7]
• Bromodomain, CBP[1103–1175], P300[1067–1139]^[7]
• CH2 domain, CBP[1191–1317], P300[1155-1280].^[8]
• HAT domain, CBP[1323–1700], P300[1287–1663]^[7]
• CH3/ZZ domain, CBP[1701-1744], P300[1664-1707]^[7]
• CH3/TAZ2 domain, CBP[1765–1846], P300[1728-1809]^[7]
• IRF-3 binding (i-BiD),^[9] nuclear receptor coactivator binding (NCBD),^[10] or SRC1 interaction domain (SID;),^[11] CBP[2020-2113], P300[1992-2098].

All three CH (cysteine/histidine-rich) domains are zinc fingers.^[8]

Interactions

Human and animal proteins:

Yeast proteins:

Viral proteins:

External links

• KIXBASE, a database of KIX-superfamily domains and PDB structures (HMM training dataset)

Notes and References

1. Parker D, Ferreri K, Nakajima T, LaMorte VJ, Evans R, Koerber SC, Hoeger C, Montminy MR . 6 . 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 . February 1996 . 8552098 . 231049 . 10.1128/MCB.16.2.694 .
2. Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE . 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 . November 2002 . 12205094 . 10.1074/jbc.M207660200 . free . 10.1.1.615.9401 .
3. Thakur JK, Yadav A, Yadav G . Molecular recognition by the KIX domain and its role in gene regulation . Nucleic Acids Research . 42 . 4 . 2112–25 . February 2014 . 24253305 . 3936767 . 10.1093/nar/gkt1147 .
4. Novatchkova M, Eisenhaber F . Linking transcriptional mediators via the GACKIX domain super family . Current Biology . 14 . 2 . R54-5 . January 2004 . 14738747 . 10.1016/j.cub.2003.12.042 . free .
5. Popuri V, Ramamoorthy M, Tadokoro T, Singh DK, Karmakar P, Croteau DL, Bohr VA . Recruitment and retention dynamics of RECQL5 at DNA double strand break sites . DNA Repair . 11 . 7 . 624–35 . July 2012 . 22633600 . 3374033 . 10.1016/j.dnarep.2012.05.001 .
6. Yadav A, Thakur JK, Yadav G . KIXBASE: A comprehensive web resource for identification and exploration of KIX domains . Scientific Reports . 7 . 1 . 14924 . November 2017 . 29097748 . 5668377 . 10.1038/s41598-017-14617-0 . 2017NatSR...714924Y .
7. [UniProt]
8. Park S, Martinez-Yamout MA, Dyson HJ, Wright PE . The CH2 domain of CBP/p300 is a novel zinc finger . FEBS Letters . 587 . 16 . 2506–11 . August 2013 . 23831576 . 3765250 . 10.1016/j.febslet.2013.06.051 . Jane Dyson .
9. Lin CH, Hare BJ, Wagner G, Harrison SC, Maniatis T, Fraenkel E . A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies . Molecular Cell . 8 . 3 . 581–90 . September 2001 . 11583620 . 10.1016/S1097-2765(01)00333-1 . free .
10. Demarest SJ, Deechongkit S, Dyson HJ, Evans RM, Wright PE . Packing, specificity, and mutability at the binding interface between the p160 coactivator and CREB-binding protein . Protein Science . 13 . 1 . 203–10 . January 2004 . 14691235 . 2286511 . 10.1110/ps.03366504 .
11. Sheppard HM, Harries JC, Hussain S, Bevan C, Heery DM . 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 . January 2001 . 11113179 . 86566 . 10.1128/MCB.21.1.39-50.2001 .