Deciphering the molecular mechanisms underlying the binding of the TWIST1/E12 complex to regulatory E-box sequences
| Autor: | Mylène Honorat, Léa Payen, Alain Puisieux, Brigitte Manship, Charlotte Bouard, Stéphane Ansieau, Raphaël Terreux, Arnaud Vigneron |
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| Přispěvatelé: | Manship, Brigitte, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Hospices Civils de Lyon (HCL) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine In silico [SDV]Life Sciences [q-bio] Molecular Conformation E-box Plasma protein binding Molecular Dynamics Simulation Biology Cell Line E-Box Elements Transcription Factor 3 03 medical and health sciences chemistry.chemical_compound Structural Biology Genetics Humans Binding site Transcription factor ComputingMilieux_MISCELLANEOUS Binding Sites Base Sequence Twist-Related Protein 1 Hydrogen Bonding Molecular Docking Simulation [SDV] Life Sciences [q-bio] 030104 developmental biology chemistry Docking (molecular) DNA Protein Binding |
| Zdroj: | Nucleic Acids Research Nucleic Acids Research, 2016, 44 (11), pp.5470-5489. ⟨10.1093/nar/gkw334⟩ |
| ISSN: | 0305-1048 1362-4962 |
| Popis: | The TWIST1 bHLH transcription factor controls embryonic development and cancer processes. Although molecular and genetic analyses have provided a wealth of data on the role of bHLH transcription factors, very little is known on the molecular mechanisms underlying their binding affinity to the E-box sequence of the promoter. Here, we used an in silico model of the TWIST1/E12 (TE) heterocomplex and performed molecular dynamics (MD) simulations of its binding to specific (TE-box) and modified E-box sequences. We focused on (i) active E-box and inactive E-box sequences, on (ii) modified active E-box sequences, as well as on (iii) two box sequences with modified adjacent bases the AT- and TA-boxes. Our in silico models were supported by functional in vitro binding assays. This exploration highlighted the predominant role of protein side-chain residues, close to the heart of the complex, at anchoring the dimer to DNA sequences, and unveiled a shift towards adjacent ((-1) and (-1*)) bases and conserved bases of modified E-box sequences. In conclusion, our study provides proof of the predictive value of these MD simulations, which may contribute to the characterization of specific inhibitors by docking approaches, and their use in pharmacological therapies by blocking the tumoral TWIST1/E12 function in cancers. |
| Databáze: | OpenAIRE |
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