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 being comprised 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> 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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[[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>.
=== 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> Schott, J., Benson, D., Basson, C., Pease, W., Silberbach, G., Moak, J., Maron, B., Seidman, C., and Seidman, J. (1998) Congenital heart disease caused by mutations in the transcription factor NKX2−5. Science 281, 108−111. </ref>,<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> 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

Revision as of 21:12, 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.
  2. ↑ Bürglin, T. R., & Affolter, M. (2016). Homeodomain proteins: an update. Chromosoma, 125(3), 497–521. https://doi.org/10.1007/s00412-015-0543-8
  3. ↑ 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
  4. ↑ 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.
  5. ↑ Olson, E. N. (2006) Gene regulatory networks in the evolution and development of the heart. Science 313, 1922−1927.
  6. ↑ Akazawa H, Komuro I. Cardiac transcription factor Csx/Nkx2–5: Its role in cardiac development and diseases. Pharmacol Ther. 2005;107:252–268.
  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., 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.
  8. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Schott
  9. ↑ 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

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