| Structural highlights
Disease
[FOXO4_HUMAN] A chromosomal aberration involving FOXO4 is found in acute leukemias. Translocation t(X;11)(q13;q23) with KMT2A/MLL1. The result is a rogue activator protein.
Function
[FOXO4_HUMAN] Transcription factor involved in the regulation of the insulin signaling pathway. Binds to insulin-response elements (IREs) and can activate transcription of IGFBP1. Down-regulates expression of HIF1A and suppresses hypoxia-induced transcriptional activation of HIF1A-modulated genes. Also involved in negative regulation of the cell cycle. Involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity.[1] [2] [3] [4] [5] [6] [7] [8]
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
FOXO4 is a member of the FOXO subgroup of forkhead transcription factors that constitute key components of a conserved signalling pathway that connects growth and stress signals to transcriptional control. Here, the 1.9 A resolution crystal structure of the DNA-binding domain of human FOXO4 (FOXO4-DBD) bound to a 13 bp DNA duplex containing a FOXO consensus binding sequence is reported. The structure shows a similar recognition of the core sequence as has been shown for two other FOXO proteins. Helix H3 is docked into the major groove and provides all of the base-specific contacts, while the N-terminus and wing W1 make additional contacts with the phosphate groups of DNA. In contrast to other FOXO-DBD-DNA structures, the loop between helices H2 and H3 has a different conformation and participates in DNA binding. In addition, the structure of the FOXO4-DBD-DNA complex suggests that both direct water-DNA base contacts and the unique water-network interactions contribute to FOXO-DBD binding to the DNA in a sequence-specific manner.
Structure of the human FOXO4-DBD-DNA complex at 1.9 A resolution reveals new details of FOXO binding to the DNA.,Boura E, Rezabkova L, Brynda J, Obsilova V, Obsil T Acta Crystallogr D Biol Crystallogr. 2010 Dec;66(Pt 12):1351-7. Epub 2010, Nov 16. PMID:21123876[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature. 1999 Apr 15;398(6728):630-4. PMID:10217147 doi:http://dx.doi.org/10.1038/19328
- ↑ Medema RH, Kops GJ, Bos JL, Burgering BM. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature. 2000 Apr 13;404(6779):782-7. PMID:10783894 doi:http://dx.doi.org/10.1038/35008115
- ↑ Tang TT, Lasky LA. The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism. J Biol Chem. 2003 Aug 8;278(32):30125-35. Epub 2003 May 21. PMID:12761217 doi:http://dx.doi.org/10.1074/jbc.M302042200
- ↑ van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004 Jul 9;279(28):28873-9. Epub 2004 May 4. PMID:15126506 doi:10.1074/jbc.M401138200
- ↑ Liu ZP, Wang Z, Yanagisawa H, Olson EN. Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev Cell. 2005 Aug;9(2):261-70. PMID:16054032 doi:http://dx.doi.org/S1534-5807(05)00213-3
- ↑ van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol. 2006 Oct;8(10):1064-73. Epub 2006 Sep 10. PMID:16964248 doi:10.1038/ncb1469
- ↑ Szypowska AA, de Ruiter H, Meijer LA, Smits LM, Burgering BM. Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-like kinase. Antioxid Redox Signal. 2011 Feb 15;14(4):563-78. doi: 10.1089/ars.2010.3243. Epub, 2010 Nov 23. PMID:20874444 doi:http://dx.doi.org/10.1089/ars.2010.3243
- ↑ Vilchez D, Boyer L, Morantte I, Lutz M, Merkwirth C, Joyce D, Spencer B, Page L, Masliah E, Berggren WT, Gage FH, Dillin A. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature. 2012 Sep 13;489(7415):304-8. doi: 10.1038/nature11468. PMID:22972301 doi:http://dx.doi.org/10.1038/nature11468
- ↑ Boura E, Rezabkova L, Brynda J, Obsilova V, Obsil T. Structure of the human FOXO4-DBD-DNA complex at 1.9 A resolution reveals new details of FOXO binding to the DNA. Acta Crystallogr D Biol Crystallogr. 2010 Dec;66(Pt 12):1351-7. Epub 2010, Nov 16. PMID:21123876 doi:10.1107/S0907444910042228
|
