NKX2.5 Homeodomain
From Proteopedia
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DNA-binding is mediated by residues of <scene name='91/911264/Major_groove_interaction/4'>alpha-helix three</scene> probing into the major groove. In the structure presented, NKX2.5 is binding to a known target: the ANF-242 sequence downstream of the atrial natriuretic factor peptide promoter <ref name="Schott" />. The ANF-242 site contains two NK family binding motifs, <scene name='91/911264/Nk_motif/1'>AAGTG</scene>, separated by a five nucelotide gap <ref> PMID: 21930795 </ref>. NKX2.5 interacts to this motif with residues positioned on alpha helix 3. Thre residues, <scene name='91/911264/Dna-backbone_interactions/1'>Gln 187, Arg 190 and Lys 194</scene> interact with DNA backbone at the NK binding motif. Interactions to bases in the major groove is mediated by two residues: <scene name='91/911264/Major_groove_interactions/2'>Asn 188 and Tyr 191</scene>. In addition to these two major grove interactions, there are three additional reidues that interact with bases in the NK motif. These bases are <scene name='91/911264/Other_residues/1'>Arg 142, Ile 184 and Gln 50</scene>. These residues are of particular importance as mutations in this region has been directly linked to pathologies discussed above <ref name="Schott" />,<ref> PMID: 26926761 </ref>. | DNA-binding is mediated by residues of <scene name='91/911264/Major_groove_interaction/4'>alpha-helix three</scene> probing into the major groove. In the structure presented, NKX2.5 is binding to a known target: the ANF-242 sequence downstream of the atrial natriuretic factor peptide promoter <ref name="Schott" />. The ANF-242 site contains two NK family binding motifs, <scene name='91/911264/Nk_motif/1'>AAGTG</scene>, separated by a five nucelotide gap <ref> PMID: 21930795 </ref>. NKX2.5 interacts to this motif with residues positioned on alpha helix 3. Thre residues, <scene name='91/911264/Dna-backbone_interactions/1'>Gln 187, Arg 190 and Lys 194</scene> interact with DNA backbone at the NK binding motif. Interactions to bases in the major groove is mediated by two residues: <scene name='91/911264/Major_groove_interactions/2'>Asn 188 and Tyr 191</scene>. In addition to these two major grove interactions, there are three additional reidues that interact with bases in the NK motif. These bases are <scene name='91/911264/Other_residues/1'>Arg 142, Ile 184 and Gln 50</scene>. These residues are of particular importance as mutations in this region has been directly linked to pathologies discussed above <ref name="Schott" />,<ref> PMID: 26926761 </ref>. | ||
- | === Protein / Protein === | + | === Protein / Protein Interactions=== |
- | The global structure of NKX2.5 is maintained by both hydrophobic and hydrophilic interactions between the three alpha-helices. This is clear when observing the structure of NKX2.5 where <scene name='91/911264/Hydrophilic_and_phobic/1'>coloring is based on hydrophobicity</scene>. Besides these tertiary interactions present in NKX2.5, the protein is known to associate with other transcription factors and regulatory proteins. For example, GATA factors, and the Hand1 transcription factor (both of which are important in cardiogenesis) are known to interact with NKX2.5 <ref> PMID: 9312027 </ref>,<ref> PMID: 21519287 </ref>. Unfortunately, structures are not available for these complexes. Structures have been elucidated for the interaction of <scene name='91/911264/Tbx5/1'>NKX2.5 with the transcription factor TBX5</scene> (T-box5)<ref> PMID: 26926761 </ref>. | + | The global structure of NKX2.5 is maintained by both hydrophobic and hydrophilic interactions between the three alpha-helices. This is clear when observing the structure of NKX2.5 where <scene name='91/911264/Hydrophilic_and_phobic/1'>coloring is based on hydrophobicity</scene>. Besides these tertiary interactions present in NKX2.5, the protein is known to associate with other transcription factors and regulatory proteins. For example, GATA factors, and the Hand1 transcription factor (both of which are important in cardiogenesis) are known to interact with NKX2.5 <ref> PMID: 9312027 </ref>,<ref> PMID: 21519287 </ref>. Unfortunately, structures are not available for these complexes. Structures have been elucidated for the interaction of <scene name='91/911264/Tbx5/1'>NKX2.5 with the transcription factor TBX5</scene> (T-box5)<ref> PMID: 26926761 </ref>. This interaction appears is thought to be mediated <scene name='91/911264/Tbx5_interactions/1'>through three residues</scene>: Lys 158 of NKX2.5 along with Asp 140 and Pro 142 from TBX5. |
Revision as of 19:11, 4 May 2022
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References
- ↑ Gehring WJ, Affolter M, Burglin T. Homeodomain proteins. Annu Rev Biochem. 1994;63:487-526. doi: 10.1146/annurev.bi.63.070194.002415. PMID:7979246 doi:http://dx.doi.org/10.1146/annurev.bi.63.070194.002415
- ↑ Burglin TR, Affolter M. Homeodomain proteins: an update. Chromosoma. 2016 Jun;125(3):497-521. doi: 10.1007/s00412-015-0543-8. Epub 2015, Oct 13. PMID:26464018 doi:http://dx.doi.org/10.1007/s00412-015-0543-8
- ↑ Pradhan L, Genis C, Scone P, Weinberg EO, Kasahara H, Nam HJ. Crystal structure of the human NKX2.5 homeodomain in complex with DNA target. Biochemistry. 2012 Aug 14;51(32):6312-9. Epub 2012 Aug 3. PMID:22849347 doi:http://dx.doi.org/10.1021/bi300849c
- ↑ 4.0 4.1 4.2 4.3 Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 1998 Jul 3;281(5373):108-11. PMID:9651244
- ↑ 5.0 5.1 Gittenberger-de Groot AC, Bartelings MM, Deruiter MC, Poelmann RE. Basics of cardiac development for the understanding of congenital heart malformations. Pediatr Res. 2005 Feb;57(2):169-76. doi: 10.1203/01.PDR.0000148710.69159.61. Epub, 2004 Dec 20. PMID:15611355 doi:http://dx.doi.org/10.1203/01.PDR.0000148710.69159.61
- ↑ Olson EN. Gene regulatory networks in the evolution and development of the heart. Science. 2006 Sep 29;313(5795):1922-7. doi: 10.1126/science.1132292. PMID:17008524 doi:http://dx.doi.org/10.1126/science.1132292
- ↑ Akazawa H, Komuro I. Cardiac transcription factor Csx/Nkx2-5: Its role in cardiac development and diseases. Pharmacol Ther. 2005 Aug;107(2):252-68. doi: 10.1016/j.pharmthera.2005.03.005. PMID:15925411 doi:http://dx.doi.org/10.1016/j.pharmthera.2005.03.005
- ↑ Toko H, Zhu W, Takimoto E, Shiojima I, Hiroi Y, Zou Y, Oka T, Akazawa H, Mizukami M, Sakamoto M, Terasaki F, Kitaura Y, Takano H, Nagai T, Nagai R, Komuro I. Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart. J Biol Chem. 2002 Jul 5;277(27):24735-43. doi: 10.1074/jbc.M107669200. Epub 2002 , Mar 11. PMID:11889119 doi:http://dx.doi.org/10.1074/jbc.M107669200
- ↑ McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol. 2003 Nov 5;42(9):1650-5. doi: 10.1016/j.jacc.2003.05.004. PMID:14607454 doi:http://dx.doi.org/10.1016/j.jacc.2003.05.004
- ↑ Carlson, B. M. (1994). Human embryology and developmental biology. St. Louis: Mosby.
- ↑ Tanaka M, Chen Z, Bartunkova S, Yamasaki N, Izumo S. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development. 1999 Mar;126(6):1269-80. doi: 10.1242/dev.126.6.1269. PMID:10021345 doi:http://dx.doi.org/10.1242/dev.126.6.1269
- ↑ Furtado MB, Wilmanns JC, Chandran A, Tonta M, Biben C, Eichenlaub M, Coleman HA, Berger S, Bouveret R, Singh R, Harvey RP, Ramialison M, Pearson JT, Parkington HC, Rosenthal NA, Costa MW. A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels. Differentiation. 2016 Jan-Mar;91(1-3):29-41. doi: 10.1016/j.diff.2015.12.003., Epub 2016 Feb 17. PMID:26897459 doi:http://dx.doi.org/10.1016/j.diff.2015.12.003
- ↑ Durocher D, Chen CY, Ardati A, Schwartz RJ, Nemer M. The atrial natriuretic factor promoter is a downstream target for Nkx-2.5 in the myocardium. Mol Cell Biol. 1996 Sep;16(9):4648-55. doi: 10.1128/MCB.16.9.4648. PMID:8756621 doi:http://dx.doi.org/10.1128/MCB.16.9.4648
- ↑ Warren SA, Terada R, Briggs LE, Cole-Jeffrey CT, Chien WM, Seki T, Weinberg EO, Yang TP, Chin MT, Bungert J, Kasahara H. Differential role of Nkx2-5 in activation of the atrial natriuretic factor gene in the developing versus failing heart. Mol Cell Biol. 2011 Nov;31(22):4633-45. doi: 10.1128/MCB.05940-11. Epub 2011 Sep , 19. PMID:21930795 doi:http://dx.doi.org/10.1128/MCB.05940-11
- ↑ 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
- ↑ Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M. The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J. 1997 Sep 15;16(18):5687-96. doi: 10.1093/emboj/16.18.5687. PMID:9312027 doi:http://dx.doi.org/10.1093/emboj/16.18.5687
- ↑ Wang J, Lu Y, Chen H, Yin M, Yu T, Fu Q. Investigation of somatic NKX2-5, GATA4 and HAND1 mutations in patients with tetralogy of Fallot. Pathology. 2011 Jun;43(4):322-6. doi: 10.1097/PAT.0b013e32834635a9. PMID:21519287 doi:http://dx.doi.org/10.1097/PAT.0b013e32834635a9
- ↑ 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