5flv

Crystal structure of NKX2-5 and TBX5 bound to the Nppa promoter regionCrystal structure of NKX2-5 and TBX5 bound to the Nppa promoter region

Structural highlights

5flv is a 12 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.005Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NKX25_MOUSE Transcription factor required for the development of the heart and the spleen (PubMed:9584153, PubMed:19483677, PubMed:22560297). During heart development, acts as a transcriptional activator of NPPA/ANF in cooperation with GATA4 (PubMed:9584153). May cooperate with TBX2 to negatively modulate expression of NPPA/ANF in the atrioventricular canal (PubMed:12023302). Binds to the core DNA motif of NPPA promoter (PubMed:19483677). Together with PBX1, required for spleen development through a mechanism that involves CDKN2B repression (PubMed:22560297). Positively regulates transcription of genes such as COL3A1 and MMP2, resulting in increased pulmonary endothelial fibrosis in response to hypoxia (By similarity).[UniProtKB:P52952]^[1] ^[2] ^[3] ^[4] TBX5_MOUSE DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation. Binds to the core DNA motif of NPPA promoter.[UniProtKB:Q99593]

Publication Abstract from PubMed

Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been proposed as a mechanism for human congenital heart defects. We report extensive and complex interdependent genomic occupancy of TBX5, NKX2-5, and the zinc finger TF GATA4 coordinately controlling cardiac gene expression, differentiation, and morphogenesis. Interdependent binding serves not only to co-regulate gene expression but also to prevent TFs from distributing to ectopic loci and activate lineage-inappropriate genes. We define preferential motif arrangements for TBX5 and NKX2-5 cooperative binding sites, supported at the atomic level by their co-crystal structure bound to DNA, revealing a direct interaction between the two factors and induced DNA bending. Complex interdependent binding mechanisms reveal tightly regulated TF genomic distribution and define a combinatorial logic for heterotypic TF regulation of differentiation.

Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis.,Luna-Zurita L, Stirnimann CU, Glatt S, Kaynak BL, Thomas S, Baudin F, Samee MA, He D, Small EM, Mileikovsky M, Nagy A, Holloway AK, Pollard KS, Muller CW, Bruneau BG Cell. 2016 Feb 25;164(5):999-1014. doi: 10.1016/j.cell.2016.01.004. Epub 2016 Feb, 11. PMID:26875865^[5]

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

References

↑ Habets PE, Moorman AF, Clout DE, van Roon MA, Lingbeek M, van Lohuizen M, Campione M, Christoffels VM. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev. 2002 May 15;16(10):1234-46. PMID:12023302 doi:10.1101/gad.222902
↑ Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, Kaneda Y. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009 Jul 9;460(7252):287-91. doi: 10.1038/nature08086. Epub 2009 May 31. PMID:19483677 doi:http://dx.doi.org/10.1038/nature08086
↑ Koss M, Bolze A, Brendolan A, Saggese M, Capellini TD, Bojilova E, Boisson B, Prall OW, Elliott DA, Solloway M, Lenti E, Hidaka C, Chang CP, Mahlaoui N, Harvey RP, Casanova JL, Selleri L. Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Dev Cell. 2012 May 15;22(5):913-26. doi: 10.1016/j.devcel.2012.02.009. Epub 2012 , May 3. PMID:22560297 doi:http://dx.doi.org/10.1016/j.devcel.2012.02.009
↑ Lee Y, Shioi T, Kasahara H, Jobe SM, Wiese RJ, Markham BE, Izumo S. The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Mol Cell Biol. 1998 Jun;18(6):3120-9. PMID:9584153 doi:10.1128/MCB.18.6.3120
↑ Luna-Zurita L, Stirnimann CU, Glatt S, Kaynak BL, Thomas S, Baudin F, Samee MA, He D, Small EM, Mileikovsky M, Nagy A, Holloway AK, Pollard KS, Muller CW, Bruneau BG. Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis. Cell. 2016 Feb 25;164(5):999-1014. doi: 10.1016/j.cell.2016.01.004. Epub 2016 Feb, 11. PMID:26875865 doi:http://dx.doi.org/10.1016/j.cell.2016.01.004

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OCA

[1] Habets PE, Moorman AF, Clout DE, van Roon MA, Lingbeek M, van Lohuizen M, Campione M, Christoffels VM. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev. 2002 May 15;16(10):1234-46. PMID:12023302 doi:10.1101/gad.222902

[2] Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, Kaneda Y. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009 Jul 9;460(7252):287-91. doi: 10.1038/nature08086. Epub 2009 May 31. PMID:19483677 doi:http://dx.doi.org/10.1038/nature08086

[3] Koss M, Bolze A, Brendolan A, Saggese M, Capellini TD, Bojilova E, Boisson B, Prall OW, Elliott DA, Solloway M, Lenti E, Hidaka C, Chang CP, Mahlaoui N, Harvey RP, Casanova JL, Selleri L. Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Dev Cell. 2012 May 15;22(5):913-26. doi: 10.1016/j.devcel.2012.02.009. Epub 2012 , May 3. PMID:22560297 doi:http://dx.doi.org/10.1016/j.devcel.2012.02.009

[4] Lee Y, Shioi T, Kasahara H, Jobe SM, Wiese RJ, Markham BE, Izumo S. The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Mol Cell Biol. 1998 Jun;18(6):3120-9. PMID:9584153 doi:10.1128/MCB.18.6.3120

[5] Luna-Zurita L, Stirnimann CU, Glatt S, Kaynak BL, Thomas S, Baudin F, Samee MA, He D, Small EM, Mileikovsky M, Nagy A, Holloway AK, Pollard KS, Muller CW, Bruneau BG. Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis. Cell. 2016 Feb 25;164(5):999-1014. doi: 10.1016/j.cell.2016.01.004. Epub 2016 Feb, 11. PMID:26875865 doi:http://dx.doi.org/10.1016/j.cell.2016.01.004

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