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| | ==Crystal structure of the human FOXO3a-DBD bound to DNA== | | ==Crystal structure of the human FOXO3a-DBD bound to DNA== |
| - | <StructureSection load='2uzk' size='340' side='right' caption='[[2uzk]], [[Resolution|resolution]] 2.70Å' scene=''> | + | <StructureSection load='2uzk' size='340' side='right'caption='[[2uzk]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2uzk]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2UZK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2UZK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2uzk]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2UZK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2UZK FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2uzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uzk OCA], [http://pdbe.org/2uzk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2uzk RCSB], [http://www.ebi.ac.uk/pdbsum/2uzk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2uzk ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2uzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uzk OCA], [https://pdbe.org/2uzk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2uzk RCSB], [https://www.ebi.ac.uk/pdbsum/2uzk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2uzk ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/FOXO3_HUMAN FOXO3_HUMAN] Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with MLL/HRX. |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/FOXO3_HUMAN FOXO3_HUMAN] Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation.<ref>PMID:10102273</ref> <ref>PMID:16751106</ref> <ref>PMID:21329882</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Forkhead box protein|Forkhead box protein]] | + | *[[FOX 3D structures|FOX 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hsiao, C D]] | + | [[Category: Large Structures]] |
| - | [[Category: Huang, C Y]] | + | [[Category: Hsiao C-D]] |
| - | [[Category: Hung, M C]] | + | [[Category: Huang C-Y]] |
| - | [[Category: Sun, Y J]] | + | [[Category: Hung M-C]] |
| - | [[Category: Tsai, K L]] | + | [[Category: Sun Y-J]] |
| - | [[Category: Yang, J Y]] | + | [[Category: Tsai K-L]] |
| - | [[Category: Activator]]
| + | [[Category: Yang J-Y]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Chromosomal rearrangement]]
| + | |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Dna-binding domain]]
| + | |
| - | [[Category: Forkhead transcription factor]]
| + | |
| - | [[Category: Nuclear protein]]
| + | |
| - | [[Category: Phosphorylation]]
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| - | [[Category: Proto-oncogene]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | [[Category: Winged helix]]
| + | |
| Structural highlights
Disease
FOXO3_HUMAN Note=A chromosomal aberration involving FOXO3 is found in secondary acute leukemias. Translocation t(6;11)(q21;q23) with MLL/HRX.
Function
FOXO3_HUMAN Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation.[1] [2] [3]
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
FOXO3a is a transcription factor of the FOXO family. The FOXO proteins participate in multiple signaling pathways, and their transcriptional activity is regulated by several post-translational mechanisms, including phosphorylation, acetylation and ubiquitination. Because these post-translational modification sites are located within the C-terminal basic region of the FOXO DNA-binding domain (FOXO-DBD), it is possible that these post-translational modifications could alter the DNA-binding characteristics. To understand how FOXO mediate transcriptional activity, we report here the 2.7 A crystal structure of the DNA-binding domain of FOXO3a (FOXO3a-DBD) bound to a 13-bp DNA duplex containing a FOXO consensus binding sequence (GTAAACA). Based on a unique structural feature in the C-terminal region and results from biochemical and mutational studies, our studies may explain how FOXO-DBD C-terminal phosphorylation by protein kinase B (PKB) or acetylation by cAMP-response element binding protein (CBP) can attenuate the DNA-binding activity and thereby reduce transcriptional activity of FOXO proteins. In addition, we demonstrate that the methyl groups of specific thymine bases within the consensus sequence are important for FOXO3a-DBD recognition of the consensus binding site.
Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification.,Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD Nucleic Acids Res. 2007;35(20):6984-94. Epub 2007 Oct 16. PMID:17940099[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19;96(6):857-68. PMID:10102273
- ↑ Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006 Jun 2;125(5):987-1001. PMID:16751106 doi:S0092-8674(06)00559-9
- ↑ Kress TR, Cannell IG, Brenkman AB, Samans B, Gaestel M, Roepman P, Burgering BM, Bushell M, Rosenwald A, Eilers M. The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol Cell. 2011 Feb 18;41(4):445-57. doi: 10.1016/j.molcel.2011.01.023. PMID:21329882 doi:10.1016/j.molcel.2011.01.023
- ↑ Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD. Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification. Nucleic Acids Res. 2007;35(20):6984-94. Epub 2007 Oct 16. PMID:17940099 doi:gkm703
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