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Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency.

Marta Rigoli1, Giovanni Spagnolli1, Giulia Lorengo1

  • 1Department CIBIO, University of Trento, Via Sommarive 9, 38121 Trento, Italy.

International Journal of Molecular Sciences
|July 27, 2022
PubMed
Summary
This summary is machine-generated.

Mutations in the p53 tetramerization domain disrupt its structure and function as a transcription factor. This study reveals how these changes affect p53

Keywords:
R337HTP53molecular dynamicstetramerization domaintransactivation assays

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • The tumor suppressor protein p53 requires a tetrameric assembly for its transcription factor activity.
  • This quaternary structure is stabilized by the tetramerization domain, which is functionally linked to the DNA-binding domain.
  • Pathogenic mutations in the tetramerization domain, like R337H, are linked to disease and affect p53 function.

Purpose of the Study:

  • To investigate the structural and functional impact of mutations in the p53 tetramerization domain.
  • To elucidate the role of specific salt-bridge interactions in stabilizing the tetramerization domain.
  • To understand how these mutations affect p53's transactivation capacity and specificity.

Main Methods:

  • Extended all-atom molecular dynamics simulations to predict structural changes.
  • Functional assays in a yeast-based model system to assess transactivation capacity and specificity.
  • Analysis of wild-type and mutant p53 proteins, including R337H, R337C, R337D, D352R, and a double mutant.

Main Results:

  • Molecular dynamics simulations showed that pathogenic mutations destabilize the p53 tetramerization domain.
  • Key electrostatic interactions between residues 337 and 352 were identified as crucial for tetramer stability.
  • Transactivation assays revealed decreased transactivation potential and altered specificity in p53 mutants, including increased tolerance for weak DNA-binding sites.

Conclusions:

  • Naturally occurring variations at positions 337 and 352 significantly impact p53's conformational stability and transcriptional function.
  • Destabilization of the tetramerization domain by mutations affects p53's ability to regulate gene expression.
  • Understanding these effects is crucial for comprehending the pathogenicity of p53 mutations in cancer and inherited diseases.