Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

Cancer-related Mutations with Local or Long-range Effects on an Allosteric Loop of p53

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Lactate-Mediated Protection of Retinal Ganglion Cells

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. The Limitations of In Vitro Experimentation in Understanding Biofilms and Chronic Infection

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Stabilizing a flexible interdomain hinge region harboring the SMB binding site drives uPAR into its closed conformation

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Crystal Structure of the Urokinase Receptor in a Ligand-Free Form

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. Quorum sensing regulation in Aeromonas hydrophila

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Changes in body mass index during treatment of childhood acute lymphoblastic leukemia with the Nordic ALL2008 protocol

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. End-of-life communication: a nationwide study of bereaved parents' perceptions

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Kristine Degn
  • Ludovica Beltrame
  • Freja Dahl Hede
  • Valentina Sora
  • Vincenzo Nicolaci
  • Marina Vabistsevits
  • Kjeld Schmiegelow
  • Karin Wadt
  • Matteo Tiberti
  • Matteo Lambrughi
  • Elena Papaleo
Vis graf over relationer

The tumor protein 53 (p53) is involved in transcription-dependent and independent processes. Several p53 variants related to cancer have been found to impact protein stability. Other variants, on the contrary, might have little impact on structural stability and have local or long-range effects on the p53 interactome. Our group previously identified a loop in the DNA binding domain (DBD) of p53 (residues 207-213) which can recruit different interactors. Experimental structures of p53 in complex with other proteins strengthen the importance of this interface for protein-protein interactions. We here characterized with structure-based approaches somatic and germline variants of p53 which could have a marginal effect in terms of stability and act locally or allosterically on the region 207-213 with consequences on the cytosolic functions of this protein. To this goal, we studied 1132 variants in the p53 DBD with structure-based approaches, accounting also for protein dynamics. We focused on variants predicted with marginal effects on structural stability. We then investigated each of these variants for their impact on DNA binding, dimerization of the p53 DBD, and intramolecular contacts with the 207-213 region. Furthermore, we identified variants that could modulate long-range the conformation of the region 207-213 using a coarse-grain model for allostery and all-atom molecular dynamics simulations. Our predictions have been further validated using enhanced sampling methods for 15 variants. The methodologies used in this study could be more broadly applied to other p53 variants or cases where conformational changes of loop regions are essential in the function of disease-related proteins.

OriginalsprogEngelsk
Artikelnummer167663
TidsskriftJournal of Molecular Biology
Vol/bind434
Udgave nummer17
Antal sider33
ISSN0022-2836
DOI
StatusUdgivet - 15 sep. 2022

Bibliografisk note

Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

ID: 79117381