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Title 

Structural convergence of unstructured p53 family transactivation domains in mdm2 recognition

Authors 

Jae-Sun ShinJi Hyang HaDong Hwa LeeK S RyuKwang-Hee BaeByoung Chul ParkSung Goo ParkG S YiSeung-Wook Chi

Publisher 

Landes Bioscience

Issue Date 

2015

Citation 

Cell Cycle, vol. 14, no. 4, pp. 533-543

Keywords 

Complex structureMDM2NMRP53 familyP73Transactivation domain

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.

ISSN 

1538-4101

Link 

http://dx.doi.org/10.1080/15384101.2014.998056

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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