2k8f

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Structural Basis for the Regulation of p53 Function by p300

Structural highlights

2k8f is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

EP300_HUMAN Note=Defects in EP300 may play a role in epithelial cancer. Note=Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. Defects in EP300 are the cause of Rubinstein-Taybi syndrome type 2 (RSTS2) [MIM:613684. A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Some individuals with RSTS2 have less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure than RSTS1 patients.[1]

Function

EP300_HUMAN Functions as histone acetyltransferase and regulates transcription via chromatin remodeling. Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation. Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Also functions as acetyltransferase for nonhistone targets. Acetylates 'Lys-131' of ALX1 and acts as its coactivator in the presence of CREBBP. Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function. Acetylates HDAC1 leading to its inactivation and modulation of transcription. Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2. Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Acetylates FOXO1 and enhances its transcriptional activity.[2] [3] [4] [5] [6] [7] [8] [9] [10]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Coactivators CREB-binding protein and p300 play important roles in mediating the transcriptional activity of p53. Until now, however, no detailed structural information has been available on how any of the domains of p300 interact with p53. Here, we report the NMR structure of the complex of the Taz2 (C/H3) domain of p300 and the N-terminal transactivation domain of p53. In the complex, p53 forms a short alpha helix and interacts with the Taz2 domain through an extended surface. Mutational analyses demonstrate the importance of hydrophobic residues for complex stabilization. Additionally, they suggest that the increased affinity of Taz2 for p53(1-39) phosphorylated at Thr(18) is due in part to electrostatic interactions of the phosphate with neighboring arginine residues in Taz2. Thermodynamic experiments revealed the importance of hydrophobic interactions in the complex of Taz2 with p53 phosphorylated at Ser(15) and Thr(18).

Structural basis for p300 Taz2-p53 TAD1 binding and modulation by phosphorylation.,Feng H, Jenkins LM, Durell SR, Hayashi R, Mazur SJ, Cherry S, Tropea JE, Miller M, Wlodawer A, Appella E, Bai Y Structure. 2009 Feb 13;17(2):202-10. PMID:19217391[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
14 reviews cite this structure
Tumour suppression by p53: a role for the DNA damage response?
Meek et al. (2009)
13 more
50 other articles
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See Also

References

  1. ↑ Roelfsema JH, White SJ, Ariyurek Y, Bartholdi D, Niedrist D, Papadia F, Bacino CA, den Dunnen JT, van Ommen GJ, Breuning MH, Hennekam RC, Peters DJ. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am J Hum Genet. 2005 Apr;76(4):572-80. Epub 2005 Feb 10. PMID:15706485 doi:S0002-9297(07)62869-9
  2. ↑ Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, Montminy M, Evans RM. A transcriptional switch mediated by cofactor methylation. Science. 2001 Dec 21;294(5551):2507-11. Epub 2001 Nov 8. PMID:11701890 doi:10.1126/science.1065961
  3. ↑ Snowden AW, Anderson LA, Webster GA, Perkins ND. A novel transcriptional repression domain mediates p21(WAF1/CIP1) induction of p300 transactivation. Mol Cell Biol. 2000 Apr;20(8):2676-86. PMID:10733570
  4. ↑ Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hubscher U, Hottiger MO. Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. Mol Cell. 2001 Jun;7(6):1221-31. PMID:11430825
  5. ↑ Braganca J, Eloranta JJ, Bamforth SD, Ibbitt JC, Hurst HC, Bhattacharya S. Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2. J Biol Chem. 2003 May 2;278(18):16021-9. Epub 2003 Feb 12. PMID:12586840 doi:10.1074/jbc.M208144200
  6. ↑ Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T. P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain. J Bone Miner Res. 2003 Aug;18(8):1419-29. PMID:12929931 doi:http://dx.doi.org/10.1359/jbmr.2003.18.8.1419
  7. ↑ An W, Kim J, Roeder RG. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell. 2004 Jun 11;117(6):735-48. PMID:15186775 doi:10.1016/j.cell.2004.05.009
  8. ↑ Perrot V, Rechler MM. The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription. Mol Endocrinol. 2005 Sep;19(9):2283-98. Epub 2005 May 12. PMID:15890677 doi:10.1210/me.2004-0292
  9. ↑ Qiu Y, Zhao Y, Becker M, John S, Parekh BS, Huang S, Hendarwanto A, Martinez ED, Chen Y, Lu H, Adkins NL, Stavreva DA, Wiench M, Georgel PT, Schiltz RL, Hager GL. HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcription. Mol Cell. 2006 Jun 9;22(5):669-79. PMID:16762839 doi:10.1016/j.molcel.2006.04.019
  10. ↑ Han Y, Jin YH, Kim YJ, Kang BY, Choi HJ, Kim DW, Yeo CY, Lee KY. Acetylation of Sirt2 by p300 attenuates its deacetylase activity. Biochem Biophys Res Commun. 2008 Oct 31;375(4):576-80. doi:, 10.1016/j.bbrc.2008.08.042. Epub 2008 Aug 21. PMID:18722353 doi:10.1016/j.bbrc.2008.08.042
  11. ↑ Feng H, Jenkins LM, Durell SR, Hayashi R, Mazur SJ, Cherry S, Tropea JE, Miller M, Wlodawer A, Appella E, Bai Y. Structural basis for p300 Taz2-p53 TAD1 binding and modulation by phosphorylation. Structure. 2009 Feb 13;17(2):202-10. PMID:19217391 doi:10.1016/j.str.2008.12.009

Contents


PDB ID 2k8f

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