| Structural highlights
2kzu is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Related: | 2kzs |
| Gene: | DAXX, DADB-159G18.9-007, DAMC-227D19.15-007, DAQB-126H3.2-007, XXbac-BCX165D10.3-007, XXbac-BPG185D15.6-007 (HUMAN), RASSF1, hCG_17462 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Function
[RASF1_HUMAN] Potential tumor suppressor. Required for death receptor-dependent apoptosis. Mediates activation of STK3/MST2 and STK4/MST1 during Fas-induced apoptosis by preventing their dephosphorylation. When associated with MOAP1, promotes BAX conformational change and translocation to mitochondrial membranes in response to TNF and TNFSF10 stimulation. Isoform A interacts with CDC20, an activator of the anaphase-promoting complex, APC, resulting in the inhibition of APC activity and mitotic progression. Inhibits proliferation by negatively regulating cell cycle progression at the level of G1/S-phase transition by regulating accumulation of cyclin D1 protein. Isoform C has been shown not to perform these roles, no function has been identified for this isoform. Isoform A disrupts interactions among MDM2, DAXX and USP7, thus contributing to the efficient activation of TP53 by promoting MDM2 self-ubiquitination in cell-cycle checkpoint control in response to DNA damage.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
DAXX is a scaffold protein with diverse roles including transcription and cell cycle regulation. Using NMR spectroscopy, we demonstrate that the C-terminal half of DAXX is intrinsically disordered, whereas a folded domain is present near its N terminus. This domain forms a left-handed four-helix bundle (H1, H2, H4, H5). However, due to a crossover helix (H3), this topology differs from that of the Sin3 PAH domain, which to date has been used as a model for DAXX. The N-terminal residues of the tumor suppressor Rassf1C fold into an amphipathic alpha helix upon binding this DAXX domain via a shallow cleft along the flexible helices H2 and H5 (K(D) approximately 60 muM). Based on a proposed DAXX recognition motif as hydrophobic residues preceded by negatively charged groups, we found that peptide models of p53 and Mdm2 also bound the helical bundle. These data provide a structural foundation for understanding the diverse functions of DAXX.
Structural Characterization of the DAXX N-Terminal Helical Bundle Domain and Its Complex with Rassf1C.,Escobar-Cabrera E, Lau DK, Giovinazzi S, Ishov AM, McIntosh LP Structure. 2010 Dec 8;18(12):1642-53. PMID:21134643[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet. 2000 Jul;25(3):315-9. PMID:10888881 doi:https://dx.doi.org/10.1038/77083
- ↑ Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M, Minna JD. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst. 2001 May 2;93(9):691-9. PMID:11333291
- ↑ Shivakumar L, Minna J, Sakamaki T, Pestell R, White MA. The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation. Mol Cell Biol. 2002 Jun;22(12):4309-18. PMID:12024041
- ↑ Song MS, Song SJ, Ayad NG, Chang JS, Lee JH, Hong HK, Lee H, Choi N, Kim J, Kim H, Kim JW, Choi EJ, Kirschner MW, Lim DS. The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex. Nat Cell Biol. 2004 Feb;6(2):129-37. Epub 2004 Jan 25. PMID:14743218 doi:https://dx.doi.org/10.1038/ncb1091
- ↑ Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem J. 2004 Jul 15;381(Pt 2):453-62. PMID:15109305 doi:https://dx.doi.org/10.1042/BJ20040025
- ↑ Baksh S, Tommasi S, Fenton S, Yu VC, Martins LM, Pfeifer GP, Latif F, Downward J, Neel BG. The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death. Mol Cell. 2005 Jun 10;18(6):637-50. PMID:15949439 doi:https://dx.doi.org/S1097-2765(05)01316-X
- ↑ Oh HJ, Lee KK, Song SJ, Jin MS, Song MS, Lee JH, Im CR, Lee JO, Yonehara S, Lim DS. Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis. Cancer Res. 2006 Mar 1;66(5):2562-9. PMID:16510573 doi:https://dx.doi.org/66/5/2562
- ↑ Song MS, Song SJ, Kim SY, Oh HJ, Lim DS. The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J. 2008 Jul 9;27(13):1863-74. doi: 10.1038/emboj.2008.115. Epub 2008 Jun 19. PMID:18566590 doi:https://dx.doi.org/10.1038/emboj.2008.115
- ↑ Guo C, Zhang X, Pfeifer GP. The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian STE20-like kinases MST1 and MST2. J Biol Chem. 2011 Feb 25;286(8):6253-61. doi: 10.1074/jbc.M110.178210. Epub 2011 , Jan 3. PMID:21199877 doi:https://dx.doi.org/10.1074/jbc.M110.178210
- ↑ Escobar-Cabrera E, Lau DK, Giovinazzi S, Ishov AM, McIntosh LP. Structural Characterization of the DAXX N-Terminal Helical Bundle Domain and Its Complex with Rassf1C. Structure. 2010 Dec 8;18(12):1642-53. PMID:21134643 doi:10.1016/j.str.2010.09.016
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