Interhelical loops within the bHLH domain are determinant in maintaining TWIST1–DNA complexes

<div><p>The basic helix-loop-helix (bHLH) transcription factor TWIST1 is essential to embryonic development, and hijacking of its function contributes to the development of numerous cancer types. It forms either a homodimer or a heterodimeric complex with an E2A or HAND partner. These functionally distinct complexes display sometimes antagonistic functions during development, so that alterations in the balance between them lead to pronounced morphological alterations, as observed in mice and in Saethre–Chotzen syndrome patients. We, here, describe the structures of TWIST1 bHLH–DNA complexes produced <i>in silico</i> through molecular dynamics simulations. We highlight the determinant role of the interhelical loops in maintaining the TWIST1–DNA complex structures and provide a structural explanation for the loss of function associated with several TWIST1 mutations/insertions observed in Saethre–Chotzen syndrome patients.</p><p>An animated interactive 3D complement (I3DC) is available in Proteopedia at <a href="http://proteopedia.org/w/Journal:JBSD:27" target="_blank">http://proteopedia.org/w/Journal:JBSD:27</a></p></div

Additional file 1: Figure S1. of Destabilization of the TWIST1/E12 complex dimerization following the R154P point-mutation of TWIST1: an in silico approach

Consequence of impaired TWIST1/E12 (TE) dimerization on DNA binding. a-c: Dictionary of secondary structure of proteins (DSSP) parameters were calculated for the TE and TE R154P models, to obtain information on secondary structure and solvent accessibility of TWIST1 and E12 residues. (a) Bar chart presenting the variation in solvent accessibility of TWIST1 residues. (b) 3D representation of the conserved TWIST1 (grey ribbon)/E12 (green ribbon) complex displaying residue 154 represented in cartoon and residues impacted by DSSP calculations represented in CPK. (c) Bar chart presenting the variation in solvent accessibility of E12 residues. (PDF 196 kb