Destabilization of the TWIST1/E12 complex dimerization following the R154P point-mutation of TWIST1: an in silico approach

BMC Structural Biology
Charlotte BouardLéa Payen

Abstract

The bHLH transcription factor TWIST1 plays a key role in the embryonic development and in tumorigenesis. Some loss-of-function mutations of the TWIST1 gene have been shown to cause an autosomal dominant craniosynostosis, known as the Saethre-Chotzen syndrome (SCS). Although the functional impacts of many TWIST1 mutations have been experimentally reported, little is known on the molecular mechanisms underlying their loss-of-function. In a previous study, we highlighted the predictive value of in silico molecular dynamics (MD) simulations in deciphering the molecular function of TWIST1 residues. Here, since the substitution of the arginine 154 amino acid by a glycine residue (R154G) is responsible for the SCS phenotype and the substitution of arginine 154 by a proline experimentally decreases the dimerizing ability of TWIST1, we investigated the molecular impact of this point mutation using MD approaches. Consistently, MD simulations highlighted a clear decrease in the stability of the α-helix during the dimerization of the mutated R154P TWIST1/E12 dimer compared to the wild-type TE complex, which was further confirmed in vitro using immunoassays. Our study demonstrates that MD simulations provide a structural explanation for the...Continue Reading

References

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Methods Mentioned

BETA
immunoprecipitation
X-ray
Transfection
Protein Assay
immunoprecipitation assay

Software Mentioned

MODEL Workspace
Amber
NaMD
CHARMM
MOE
VMD function Extensions , Analysis RMSD
Extensions Analysis Analysis
SWISS
AlaScan
GraphPad Prism

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