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Designed Ankyrin Repeat Proteins as a tool box for analyzing p63.

Alexander Strubel1, Philipp Münick1, Apirat Chaikuad2,3

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Designed Ankyrin Repeat Proteins (DARPins) target p63 protein domains, enabling selective inhibition of transcription factors. This research reactivates p53 and reveals a negative feedback loop, offering a versatile tool for p63 research.

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Area of Science:

  • Molecular Biology
  • Protein Engineering
  • Transcription Factor Regulation

Background:

  • The p53 transcription factor family, including p63 and p73, relies on specific folded domains for function.
  • Targeting transcription factors for inhibition is challenging due to the lack of suitable binding pockets for small molecules.
  • Investigating the roles of individual protein domains is difficult using traditional genetic methods.

Purpose of the Study:

  • To characterize Designed Ankyrin Repeat Proteins (DARPins) selected for binding to p63 folded domains.
  • To assess the potential of DARPins as intracellular inhibitors for modulating transcriptional activity.
  • To explore the utility of DARPins in studying p63 function and regulation.

Main Methods:

  • Selection and characterization of DARPins binding to p63 folded domains.
  • Determination of DARPin binding affinities and specificities within the p53 family.
  • In vitro and cellular assays to evaluate DARPin-mediated inhibition of transcriptional activity.

Main Results:

  • DARPins were identified as tight binders for all folded domains of p63.
  • DARPins effectively inhibited the DNA-binding activity of the ΔNp63α isoform, leading to p53 reactivation.
  • Inhibition of p63 DNA binding stabilized p63, indicating a negative feedback mechanism.
  • DARPins demonstrated binding to various p63 conformations and could detect p63 in biological samples.

Conclusions:

  • DARPins serve as potent intracellular inhibitors for p63, modulating transcriptional activity.
  • Selective inhibition of ΔNp63α by DARPins reactivates p53 and provides insights into regulatory feedback loops.
  • The developed DARPins are versatile tools for p63 research, including detection and functional studies.