4s0h

From Proteopedia

(Difference between revisions)

Revision as of 17:11, 10 May 2016

TBX5 DB, NKX2.5 HD, ANF DNA Complex

Structural highlights

4s0h is a 8 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[TBX5_HUMAN] Holt-Oram syndrome. The disease is caused by mutations affecting the gene represented in this entry. Defects in TBX5 are associated with susceptibility to dilated cardiomyopathy (DCM). A disorder characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death.^[1] ^[2] [NKX25_HUMAN] Athyreosis;Familial isolated congenital asplenia;Atrial septal defect - atrioventricular conduction defects;Atrial septal defect, ostium secundum type;Hypoplastic left heart syndrome;Tetralogy of Fallot;Familial atrial fibrillation;Familial progressive cardiac conduction defect;Thyroid hypoplasia;Ventricular septal defect. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

[TBX5_HUMAN] DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.^[3] ^[4] ^[5] [NKX25_HUMAN] Implicated in commitment to and/or differentiation of the myocardial lineage. Acts as a transcriptional activator of ANF in cooperation with GATA4 (By similarity). It is transcriptionally controlled by PBX1 and acts as a transcriptional repressor of CDKN2B (By similarity). It is required for spleen development.^[6]

Publication Abstract from PubMed

Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N-terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be "intrinsically unstructured", and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a beta-strand conformation bridging two beta-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes.

Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5.,Pradhan L, Gopal S, Li S, Ashur S, Suryanarayanan S, Kasahara H, Nam HJ Biochemistry. 2016 Mar 29;55(12):1702-10. doi: 10.1021/acs.biochem.6b00171. Epub , 2016 Mar 9. PMID:26926761^[7]

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

References

↑ Zhang XL, Qiu XB, Yuan F, Wang J, Zhao CM, Li RG, Xu L, Xu YJ, Shi HY, Hou XM, Qu XK, Xu YW, Yang YQ. TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. Biochem Biophys Res Commun. 2015 Mar 27;459(1):166-71. doi:, 10.1016/j.bbrc.2015.02.094. Epub 2015 Feb 26. PMID:25725155 doi:http://dx.doi.org/10.1016/j.bbrc.2015.02.094
↑ Zhou W, Zhao L, Jiang JQ, Jiang WF, Yang YQ, Qiu XB. A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. Int J Mol Med. 2015 Jul;36(1):282-8. doi: 10.3892/ijmm.2015.2206. Epub 2015 May, 11. PMID:25963046 doi:http://dx.doi.org/10.3892/ijmm.2015.2206
↑ Zhang XL, Qiu XB, Yuan F, Wang J, Zhao CM, Li RG, Xu L, Xu YJ, Shi HY, Hou XM, Qu XK, Xu YW, Yang YQ. TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. Biochem Biophys Res Commun. 2015 Mar 27;459(1):166-71. doi:, 10.1016/j.bbrc.2015.02.094. Epub 2015 Feb 26. PMID:25725155 doi:http://dx.doi.org/10.1016/j.bbrc.2015.02.094
↑ Zhou W, Zhao L, Jiang JQ, Jiang WF, Yang YQ, Qiu XB. A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. Int J Mol Med. 2015 Jul;36(1):282-8. doi: 10.3892/ijmm.2015.2206. Epub 2015 May, 11. PMID:25963046 doi:http://dx.doi.org/10.3892/ijmm.2015.2206
↑ Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997 Jan;15(1):21-9. PMID:8988164 doi:http://dx.doi.org/10.1038/ng0197-21
↑ 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
↑ Pradhan L, Gopal S, Li S, Ashur S, Suryanarayanan S, Kasahara H, Nam HJ. Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5. Biochemistry. 2016 Mar 29;55(12):1702-10. doi: 10.1021/acs.biochem.6b00171. Epub , 2016 Mar 9. PMID:26926761 doi:http://dx.doi.org/10.1021/acs.biochem.6b00171

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4s0h"

Categories: Pradhan, L | Transcription factor | Transcription-dna complex

@@ Line 1: / Line 1: @@
 ==TBX5 DB, NKX2.5 HD, ANF DNA Complex==
 <StructureSection load='4s0h' size='340' side='right' caption='[[4s0h]], [[Resolution|resolution]] 2.82&Aring;' scene=''>
@@ Line 9: / Line 10: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/TBX5_HUMAN TBX5_HUMAN]] DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.<ref>PMID:25725155</ref> <ref>PMID:25963046</ref> <ref>PMID:8988164</ref>  [[http://www.uniprot.org/uniprot/NKX25_HUMAN NKX25_HUMAN]] Implicated in commitment to and/or differentiation of the myocardial lineage. Acts as a transcriptional activator of ANF in cooperation with GATA4 (By similarity). It is transcriptionally controlled by PBX1 and acts as a transcriptional repressor of CDKN2B (By similarity). It is required for spleen development.<ref>PMID:22560297</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Heart development in mammalian systems is controlled by combinatorial interactions of master cardiac transcription factors such as TBX5 and NKX2.5. They bind to promoters/enhancers of downstream targets as homo- or heteromultimeric complexes. They physically interact and synergistically regulate their target genes. To elucidate the molecular basis of the intermolecular interactions, a heterodimer and a homodimer of NKX2.5 and TBX5 were studied using X-ray crystallography. Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA and a crystal structure of TBX5 homodimer. The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5), residues that are highly conserved in TBX and NKX families across species. Extensive homodimeric interactions were observed between the TBX5 proteins in both crystal structures. In particular, in the crystal structure of TBX5 protein that includes the N-terminal and DNA binding domains, intermolecular interactions were mediated by the N-terminal domain of the protein. The N-terminal domain of TBX5 was predicted to be "intrinsically unstructured", and in one of the two molecules in an asymmetric unit, the N-terminal domain assumes a beta-strand conformation bridging two beta-sheets from the two molecules. The structures reported here may represent general mechanisms for combinatorial interactions among transcription factors regulating developmental processes.
+Intermolecular Interactions of Cardiac Transcription Factors NKX2.5 and TBX5.,Pradhan L, Gopal S, Li S, Ashur S, Suryanarayanan S, Kasahara H, Nam HJ Biochemistry. 2016 Mar 29;55(12):1702-10. doi: 10.1021/acs.biochem.6b00171. Epub , 2016 Mar 9. PMID:26926761<ref>PMID:26926761</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4s0h" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4s0h

From Proteopedia

Revision as of 17:11, 10 May 2016

TBX5 DB, NKX2.5 HD, ANF DNA Complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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