Targeting an Interaction Between Two Disordered Domains by Using a Designed Peptide

Guy Mayer, Zohar Shpilt, Shachar Bressler, Orly Marcu, Ora Schueler-Furman, Edit Y. Tshuva, Assaf Friedler

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Intrinsically disordered regions in proteins (IDRs) mediate many disease-related protein-protein interactions. However, the unfolded character and continuous conformational changes of IDRs make them difficult to target for therapeutic purposes. Here, we show that a designed peptide based on the disordered p53 linker domain can be used to target a partner IDR from the anti-apoptotic iASPP protein, promoting apoptosis of cancer cells. The p53 linker forms a hairpin-like structure with its two termini in close proximity. We designed a peptide derived from the disordered termini without the hairpin, designated as p53 LinkTer. The LinkTer peptide binds the disordered RT loop of iASPP with the same affinity as the parent p53 linker peptide, and inhibits the p53-iASPP interaction in vitro. The LinkTer peptide shows increased stability to proteolysis, penetrates cancer cells, causes nuclei shrinkage, and compromises the viability of cells. We conclude that a designed peptide comprising only the IDR from a peptide sequence can serve as an improved inhibitor since it binds its target protein without the need for pre-folding, paving the way for therapeutic targeting of IDRs.

Original languageAmerican English
Pages (from-to)10240-10249
Number of pages10
JournalChemistry - A European Journal
Volume26
Issue number45
DOIs
StatePublished - 12 Aug 2020

Bibliographical note

Publisher Copyright:
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

  • apoptosis
  • iASPP
  • intrinsically disordered regions
  • p53
  • peptides
  • protein-protein interactions

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