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Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form.

Stirnimann CU, Ptchelkine D, Grimm C, Müller CW
J Mol Biol 400 71-81 (2010)
Cited: 37 times
EuropePMC logo PMID: 20450920

Abstract

TBX5, a member of the T-box transcription factor family, plays an important role in heart and limb development. More than 60 single point or deletion mutations of human TBX5 are associated with Holt-Oram syndrome that manifests itself as heart and limb malformations in 1 out of 100,000 live births. The majority of these mutations are located in the TBX5 T-box domain. We solved the crystal structures of the human TBX5 T-box domain in its DNA-unbound form and in complex with a natural DNA target site allowing for the first time the comparison between unbound and DNA-bound forms. Our analysis identifies a 3(10)-helix at the C-terminus of the T-box domain as an inducible recognition element, critically required for the interaction with DNA, as it only forms upon DNA binding and is unstructured in the DNA-unbound form. Using circular dichroism, we characterized the thermal stability of six TBX5 mutants containing single point mutations in the T-box domain (M74V, G80R, W121G, G169R, T223M, and R237W) and compared them with wild-type protein. Mutants G80R and W121G show drastically reduced thermal stability, while the other mutants only show a marginal stability decrease. For all TBX5 mutants, binding affinities to specific and nonspecific DNA sequences were determined using isothermal titration calorimetry. All TBX5 mutants show reduced binding affinities to a specific DNA target site, although to various degrees. Interestingly, all tested TBX5 mutants differ in their ability to bind unspecific DNA, indicating that both sequence-specific and unspecific binding might contribute to the misregulation of target gene expression.

Articles - 2x6u mentioned but not cited (8)

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  4. A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice. Yook C, Kim K, Kim D, Kang H, Kim SG, Kim E, Kim SY. Front Mol Neurosci 12 241 (2019)
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Reviews citing this publication (6)

  1. The T-box gene family: emerging roles in development, stem cells and cancer. Papaioannou VE. Development 141 3819-3833 (2014)
  2. TBX5: A Key Regulator of Heart Development. Steimle JD, Moskowitz IP. Curr Top Dev Biol 122 195-221 (2017)
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  5. Molecular basis of the clinical features of Holt-Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications. Al-Qattan MM, Abou Al-Shaar H. Gene 560 129-136 (2015)
  6. Regulation of organogenesis and stem cell properties by T-box transcription factors. Takashima Y, Suzuki A. Cell Mol Life Sci 70 3929-3945 (2013)

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  3. Mapping and analysis of Caenorhabditis elegans transcription factor sequence specificities. Narasimhan K, Lambert SA, Yang AW, Riddell J, Mnaimneh S, Zheng H, Albu M, Najafabadi HS, Reece-Hoyes JS, Fuxman Bass JI, Walhout AJ, Weirauch MT, Hughes TR. Elife 4 (2015)
  4. The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation. Waldron L, Steimle JD, Greco TM, Gomez NC, Dorr KM, Kweon J, Temple B, Yang XH, Wilczewski CM, Davis IJ, Cristea IM, Moskowitz IP, Conlon FL. Dev Cell 36 262-275 (2016)
  5. Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation. Zhou L, Liu J, Olson P, Zhang K, Wynne J, Xie L. J Mol Cell Cardiol 85 1-12 (2015)
  6. KLF13 is a genetic modifier of the Holt-Oram syndrome gene TBX5. Darwich R, Li W, Yamak A, Komati H, Andelfinger G, Sun K, Nemer M. Hum Mol Genet 26 942-954 (2017)
  7. Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites. Liu CF, Brandt GS, Hoang QQ, Naumova N, Lazarevic V, Hwang ES, Dekker J, Glimcher LH, Ringe D, Petsko GA. Proc Natl Acad Sci U S A 113 E6572-E6581 (2016)
  8. Structure of the DNA-bound T-box domain of human TBX1, a transcription factor associated with the DiGeorge syndrome. El Omari K, De Mesmaeker J, Karia D, Ginn H, Bhattacharya S, Mancini EJ. Proteins 80 655-660 (2012)
  9. Function of the C. elegans T-box factor TBX-2 depends on SUMOylation. Huber P, Crum T, Clary LM, Ronan T, Packard AV, Okkema PG. Cell Mol Life Sci 70 4157-4168 (2013)
  10. The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes. Hertweck A, Vila de Mucha M, Barber PR, Dagil R, Porter H, Ramos A, Lord GM, Jenner RG. Nucleic Acids Res 50 4557-4573 (2022)
  11. A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function. Dreßen M, Lahm H, Lahm A, Wolf K, Doppler S, Deutsch MA, Cleuziou J, Pabst von Ohain J, Schön P, Ewert P, Malcic I, Lange R, Krane M. Mol Genet Genomic Med 4 557-567 (2016)
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  13. Potentiation of Tbx5-mediated transactivation by SUMO conjugation and protein inhibitor of activated STAT 1 (PIAS1). Beketaev I, Kim EY, Zhang Y, Yu W, Qian L, Wang J. Int J Biochem Cell Biol 50 82-92 (2014)
  14. The Ets factor Etv1 interacts with Tpit protein for pituitary pro-opiomelanocortin (POMC) gene transcription. Budry L, Couture C, Balsalobre A, Drouin J. J Biol Chem 286 25387-25396 (2011)
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  17. Embryonic stem cells facilitate the isolation of persistent clonal cardiovascular progenitor cell lines and leukemia inhibitor factor maintains their self-renewal and myocardial differentiation potential in vitro. Hoebaus J, Heher P, Gottschamel T, Scheinast M, Auner H, Walder D, Wiedner M, Taubenschmid J, Miksch M, Sauer T, Schultheis M, Kuzmenkin A, Seiser C, Hescheler J, Weitzer G. Cells Tissues Organs 197 249-268 (2013)
  18. Identification of a novel non-sense mutation in TBX5 gene in pediatric patients with congenital heart defects. Khatami M, Heidari MM, Kazeminasab F, Zare Bidaki R. J Cardiovasc Thorac Res 10 41-45 (2018)
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