Structural convergence of unstructured p53 family transactivation domains in MDM2 recognition

Cited 11 time in webofscience Cited 0 time in scopus
  • Hit : 419
  • Download : 0
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 -helical conformation, which is similar to the conformation of p53TAD, although the -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.
Publisher
TAYLOR & FRANCIS INC
Issue Date
2015-02
Language
English
Article Type
Article
Keywords

ACTIVATION DOMAIN; INDUCE APOPTOSIS; PROTEIN-A; P73; BINDING; P63; DEGRADATION; NMR; PHOSPHORYLATION; IDENTIFICATION

Citation

CELL CYCLE, v.14, no.4, pp.533 - 543

ISSN
1538-4101
DOI
10.1080/15384101.2014.998056
URI
http://hdl.handle.net/10203/195990
Appears in Collection
BiS-Journal Papers(저널논문)
Files in This Item
There are no files associated with this item.
This item is cited by other documents in WoS
⊙ Detail Information in WoSⓡ Click to see webofscience_button
⊙ Cited 11 items in WoS Click to see citing articles in records_button

qr_code

  • mendeley

    citeulike


rss_1.0 rss_2.0 atom_1.0