6lbi

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of FOXO1-DBD homodimer bound to a palindromic DNA sequence

Structural highlights

6lbi is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.067Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FOXO1_HUMAN Defects in FOXO1 are a cause of rhabdomyosarcoma type 2 (RMS2) [MIM:268220. It is a form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchimal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. Note=Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator.

Function

FOXO1_HUMAN Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress. Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3'. Activity suppressed by insulin. Main regulator of redox balance and osteoblast numbers and controls bone mass. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. Acts syngernistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A to activate the expression of genes such as IGFBP1, G6PC and PPCK1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and SKT4/MST1. Promotes neural cell death. Mediates insulin action on adipose. Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.

Mechanism of forkhead transcription factors binding to a novel palindromic DNA site.,Li J, Dai S, Chen X, Liang X, Qu L, Jiang L, Guo M, Zhou Z, Wei H, Zhang H, Chen Z, Chen L, Chen Y Nucleic Acids Res. 2021 Apr 6;49(6):3573-3583. doi: 10.1093/nar/gkab086. PMID:33577686^[8]

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

References

↑ Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem. 1999 Jun 11;274(24):17184-92. PMID:10358076
↑ Zhang X, Gan L, Pan H, Guo S, He X, Olson ST, Mesecar A, Adam S, Unterman TG. Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding. J Biol Chem. 2002 Nov 22;277(47):45276-84. Epub 2002 Sep 12. PMID:12228231 doi:10.1074/jbc.M208063200
↑ Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7. Epub 2004 Jun 25. PMID:15220471 doi:10.1073/pnas.0400593101
↑ 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
↑ Yuan Z, Becker EB, Merlo P, Yamada T, DiBacco S, Konishi Y, Schaefer EM, Bonni A. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science. 2008 Mar 21;319(5870):1665-8. doi: 10.1126/science.1152337. PMID:18356527 doi:10.1126/science.1152337
↑ Yuan Z, Lehtinen MK, Merlo P, Villen J, Gygi S, Bonni A. Regulation of neuronal cell death by MST1-FOXO1 signaling. J Biol Chem. 2009 Apr 24;284(17):11285-92. doi: 10.1074/jbc.M900461200. Epub 2009, Feb 16. PMID:19221179 doi:10.1074/jbc.M900461200
↑ Valis K, Prochazka L, Boura E, Chladova J, Obsil T, Rohlena J, Truksa J, Dong LF, Ralph SJ, Neuzil J. Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res. 2011 Feb 1;71(3):946-54. doi: 10.1158/0008-5472.CAN-10-2203. Epub, 2011 Jan 18. PMID:21245099 doi:10.1158/0008-5472.CAN-10-2203
↑ Li J, Dai S, Chen X, Liang X, Qu L, Jiang L, Guo M, Zhou Z, Wei H, Zhang H, Chen Z, Chen L, Chen Y. Mechanism of forkhead transcription factors binding to a novel palindromic DNA site. Nucleic Acids Res. 2021 Apr 6;49(6):3573-3583. PMID:33577686 doi:10.1093/nar/gkab086

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6lbi"

Categories: Homo sapiens | Large Structures | Chen YH | Dai SY | Li J

@@ Line 1: / Line 1: @@
-====
+==Crystal Structure of FOXO1-DBD homodimer bound to a palindromic DNA sequence==
-<StructureSection load='6lbi' size='340' side='right'caption='[[6lbi]]' scene=''>
+<StructureSection load='6lbi' size='340' side='right'caption='[[6lbi]], [[Resolution|resolution]] 3.07&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6lbi]] is a 12 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=6LBI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LBI FirstGlance]. <br>
-</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=6lbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lbi OCA], [https://pdbe.org/6lbi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lbi RCSB], [https://www.ebi.ac.uk/pdbsum/6lbi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lbi 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]] 3.067&#8491;</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=6lbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lbi OCA], [https://pdbe.org/6lbi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lbi RCSB], [https://www.ebi.ac.uk/pdbsum/6lbi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lbi ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/FOXO1_HUMAN FOXO1_HUMAN] Defects in FOXO1 are a cause of rhabdomyosarcoma type 2 (RMS2) [MIM:[https://omim.org/entry/268220 268220]. It is a form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchimal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. Note=Chromosomal aberrations involving FOXO1 are found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with PAX3 and translocation t(1;13)(p36;q14) with PAX7. The resulting protein is a transcriptional activator.
+== Function ==
+[https://www.uniprot.org/uniprot/FOXO1_HUMAN FOXO1_HUMAN] Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress. Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3'. Activity suppressed by insulin. Main regulator of redox balance and osteoblast numbers and controls bone mass. Orchestrates the endocrine function of the skeleton in regulating glucose metabolism. Acts syngernistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity. Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP. In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A to activate the expression of genes such as IGFBP1, G6PC and PPCK1. Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and SKT4/MST1. Promotes neural cell death. Mediates insulin action on adipose. Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake. Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells.<ref>PMID:10358076</ref> <ref>PMID:12228231</ref> <ref>PMID:15220471</ref> <ref>PMID:15890677</ref> <ref>PMID:18356527</ref> <ref>PMID:19221179</ref> <ref>PMID:21245099</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.
+Mechanism of forkhead transcription factors binding to a novel palindromic DNA site.,Li J, Dai S, Chen X, Liang X, Qu L, Jiang L, Guo M, Zhou Z, Wei H, Zhang H, Chen Z, Chen L, Chen Y Nucleic Acids Res. 2021 Apr 6;49(6):3573-3583. doi: 10.1093/nar/gkab086. PMID:33577686<ref>PMID:33577686</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6lbi" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[FOX 3D structures|FOX 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Z-disk]]
+[[Category: Chen YH]]
+[[Category: Dai SY]]
+[[Category: Li J]]

6lbi

From Proteopedia

Current revision

Crystal Structure of FOXO1-DBD homodimer bound to a palindromic DNA sequence

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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