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NKX2.5 Homeodomain

spinqualitylabelsall models PDB ID 3RKQ Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 General Information 1.1 Clinical Relevance 1.2 Protein / DNA Interactions 1.2.1 Mutational Analysis 2 Protein / DNA interactions 2.1 Structural highlights General Information 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. [1]. DNA-binding is mediated through the insertion of one of these 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. [2]. Clinical Relevance In the case of NKX2.5, the protein works in conjunction with multiple other transcription factors during cardiogenesis [3],[4]. 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 [5],[6],[7]. These phenotypes are speculated to arise as a result of decreased Protein / DNA Interactions Scene Mutational Analysis Protein / DNA interactions Structural highlights

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. ↑ Olson, E. N. (2006) Gene regulatory networks in the evolution and development of the heart. Science 313, 1922−1927.
4. ↑ Akazawa H, Komuro I. Cardiac transcription factor Csx/Nkx2–5: Its role in cardiac development and diseases. Pharmacol Ther. 2005;107:252–268.
5. ↑ 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.
6. ↑ 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.
7. ↑ 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