Structural convergence of unstructured p53 family transactivation domains in mdm2 recognition

Cited 20 time in scopus
Metadata Downloads
Title
Structural convergence of unstructured p53 family transactivation domains in mdm2 recognition
Author(s)
Jae-Sun Shin; Ji Hyang Ha; Dong Hwa Lee; K S Ryu; Kwang-Hee BaeByoung Chul ParkSung Goo Park; G S Yi; Seung-Wook Chi
Bibliographic Citation
Cell Cycle, vol. 14, no. 4, pp. 533-543
Publication Year
2015
Abstract
The p53, p63, and p73 proteins belong to the p53 family of transcription factors, which play key roles in tumor suppression. Although the transactivation domains (TADs) of the p53 family are intrinsically disordered, these domains are commonly involved in the regulatory interactions with mouse double minute 2 (MDM2). In this study, we determined the solution structure of the p73TAD peptide in complex with MDM2 using NMR spectroscopy and biophysically characterized the interactions between the p53 family TAD peptides and MDM2. In combination with mutagenesis data, the complex structures revealed remarkably close mimicry of the MDM2 recognition mechanism among the p53 family TADs. Upon binding with MDM2, the intrinsically disordered p73TAD and p63TAD peptides adopt an amphipathic a-helical conformation, which is similar to the conformation of p53TAD, although the a-helical content induced by MDM2 binding varies. With isothermal titration calorimetry (ITC) and circular dichroism (CD) data, our biophysical characterization showed that p73TAD resembles p53TAD more closely than p63TAD in terms of helical stability, MDM2 binding affinity, and phosphorylation effects on MDM2 binding. Therefore, our structural information may be useful in establishing alternative anticancer strategies that exploit the activation of the p73 pathway against human tumors bearing p53 mutations.
Keyword
Complex structureMDM2NMRP53 familyP73Transactivation domain
ISSN
1538-4101
Publisher
T&F (Taylor & Francis)
DOI
http://dx.doi.org/10.1080/15384101.2014.998056
Type
Article
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.