Molecular recognition of p53 and MDM2 by USP7/HAUSP

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Updated: Aug 11, 2026

Purification of Ubiquitinated p53 Proteins from Mammalian Cells
10:55

Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

Yi Sheng1, Vivian Saridakis, Feroz Sarkari

  • 1Ontario Cancer Institute, Department of Medical Biophysics, 101 College Street, Toronto, Ontario, Canada M5G 1L7.

Nature Structural & Molecular Biology
|February 14, 2006
PubMed

Insights

Ubiquitin-specific protease 7 (USP7) stabilizes p53 and MDM2 by binding specific sites. Structural and mutagenesis data reveal a P/AXXS motif critical for USP7 substrate recognition in the p53 pathway.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The ubiquitin-specific protease, USP7, plays a crucial role in regulating the p53 pathway.
  • USP7 stabilizes key tumor suppressor proteins, p53 and MDM2, impacting cellular responses to DNA damage.

Purpose of the Study:

  • To elucidate the molecular mechanism of substrate recognition by USP7.
  • To understand how USP7 interacts with p53 and MDM2.

Main Methods:

  • Cocrystallization of USP7 with p53 and MDM2 peptides.
  • X-ray crystallography to determine the binding mode.
  • Site-directed mutagenesis to identify critical residues.

Main Results:

  • USP7's N-terminal domain binds two distinct 4-residue sites in both p53 and MDM2.
  • Cocrystal structures reveal the binding interface and a conserved P/AXXS motif in substrates.
  • Serine contacts and Trp165 in USP7 are essential for peptide binding.

Conclusions:

  • USP7 recognizes its substrates, p53 and MDM2, through specific peptide motifs and binding pockets.
  • These findings provide mechanistic insights into USP7 substrate recognition and p53 pathway regulation.

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