NKX2.5 Homeodomain

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= General Information =
= General Information =
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The transcription factor, NKX2.5 is one of many proteins classified as a homeodomain, and functions to regulate structural development in eukaryotes. These proteins share a characteristic evolutionarily conserved fold containing three alpha-helices. <ref> Gehring WJ, Affolter M, Burglin T. Homeodomain proteins. Annu Rev Biochem. 1994;63:487–526. </ref>. DNA-binding is mediated through the insertion of the c-terminal side <scene name='91/911264/Major_groove_interaction/2'>alpha-helix</scene> into the major groove, allowing for base-reside interactions. This allows homeodomains to locate and bind specific DNA sequences, leading to transcriptional activation or repression <ref> Bürglin, T. R., & Affolter, M. (2016). Homeodomain proteins: an update. Chromosoma, 125(3), 497–521. https://doi.org/10.1007/s00412-015-0543-8 </ref>. The homeodomain of NKX2.5 is flanked by both a N and C-terminal regulatory domain. This puts the biological protein at 324 residues with the homeodomain consisting of residues 138-197 <ref> Pradhan, L., Genis, C., Scone, P., Weinberg, E. O., Kasahara, H., & Nam, H. J. (2012). Crystal structure of the human NKX2.5 homeodomain in complex with DNA target. Biochemistry, 51(32), 6312–6319. https://doi.org/10.1021/bi300849c </ref>
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The transcription factor, NKX2.5 is one of many proteins classified as a homeodomain, and functions to regulate structural development in eukaryotes. These proteins share a characteristic evolutionarily conserved fold containing three alpha-helices. <ref> PMID: 7979246 </ref>. DNA-binding is mediated through the insertion of the c-terminal side <scene name='91/911264/Major_groove_interaction/2'>alpha-helix</scene> into the major groove, allowing for base-reside interactions. This allows homeodomains to locate and bind specific DNA sequences, leading to transcriptional activation or repression <ref> PMID: 26464018 </ref>. The homeodomain of NKX2.5 is flanked by both a N and C-terminal regulatory domain. This puts the biological protein at 324 residues with the homeodomain consisting of residues 138-197 <ref> PMID: 22849347 </ref>
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[[Image:Map.png]] Research into the structure and function of NKX2.5 has mainly been focused on the DNA-binding homeodomain, as mutations in this region have been linked to specific diseases <ref> Schott, J. J., Benson, D. W., Basson, C. T., Pease, W., Silberbach, G. M., Moak, J. P., Maron, B. J., Seidman, C. E., & Seidman, J. G. (1998). Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science (New York, N.Y.), 281(5373), 108–111.</ref>.
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[[Image:Map.png]] Research into the structure and function of NKX2.5 has mainly been focused on the DNA-binding homeodomain, as mutations in this region have been linked to specific diseases <ref name="Schott"> PMID: 9651244</ref>.
=== Clinical Relevance ===
=== Clinical Relevance ===
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In the case of NKX2.5, the protein works in conjunction with multiple other transcription factors during cardiogenesis <ref> Olson, E. N. (2006) Gene regulatory networks in the evolution and development of the heart. Science 313, 1922−1927. </ref>,<ref> Akazawa H, Komuro I. Cardiac transcription factor Csx/Nkx2–5: Its role in cardiac development and diseases. Pharmacol Ther. 2005;107:252–268. </ref>. Recently, research has been focused on NKX2.5 as mutations in the DNA binding residues, and structural support residues of the protein have been linked to congenital heart disease. Specifically, NKX2.5 mutations have been linked to etiologies involving both atrial and septal defects, deficient atrioventricular node conduction, and more complex mutations such as Tetralogy of Fallot and Hypoplastic Left Heart Syndrome <ref> 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., and Komuro, I. (2002) Csx/Nkx2−5 is required for homeostasis and survival of cardiac myocytes in the adult heart. J. Biol. Chem. 277, 24735−24743. </ref>,<ref name="Schott" />,<ref> McElhinney, D. B., Geiger, E., Blinder, J., Benson, D. W., & Goldmuntz, E. (2003). NKX2.5 mutations in patients with congenital heart disease. Journal of the American College of Cardiology, 42(9), 1650–1655. https://doi.org/10.1016/j.jacc.2003.05.004 </ref>. These phenotypes are speculated to arise as a result of decreased
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In the case of NKX2.5, the protein works in conjunction with multiple other transcription factors during cardiogenesis <ref> PMID: 17008524</ref>,<ref> PMID: 15925411 </ref>. Recently, research has been focused on NKX2.5 as mutations in the DNA binding residues, and structural support residues of the protein have been linked to congenital heart disease. Specifically, NKX2.5 mutations have been linked to etiologies involving both atrial and septal defects, deficient atrioventricular node conduction, and more complex mutations such as Tetralogy of Fallot and Hypoplastic Left Heart Syndrome <ref> PMID: 11889119</ref>,<ref name="Schott" />,<ref> PMID: 14607454 </ref>. These phenotypes are speculated to arise as a result of decreased

Revision as of 21:23, 3 May 2022

PDB ID 3RKQ

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References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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. ↑ 4.0 4.1 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. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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

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