The p53 core domain is a molten globule at low pH: functional implications of a partially unfolded structure.

The Journal of Biological Chemistry
Ana Paula D Ano BomJerson L Silva

Abstract

p53 is a transcription factor that maintains genome integrity, and its function is lost in 50% of human cancers. The majority of p53 mutations are clustered within the core domain. Here, we investigate the effects of low pH on the structure of the wild-type (wt) p53 core domain (p53C) and the R248Q mutant. At low pH, the tryptophan residue is partially exposed to the solvent, suggesting a fluctuating tertiary structure. On the other hand, the secondary structure increases, as determined by circular dichroism. Binding of the probe bis-ANS (bis-8-anilinonaphthalene-1-sulfonate) indicates that there is an increase in the exposure of hydrophobic pockets for both wt and mutant p53C at low pH. This behavior is accompanied by a lack of cooperativity under urea denaturation and decreased stability under pressure when p53C is in acidic pH. Together, these results indicate that p53C acquires a partially unfolded conformation (molten-globule state) at low pH (5.0). The hydrodynamic properties of this conformation are intermediate between the native and denatured conformation. (1)H-(15)N HSQC NMR spectroscopy confirms that the protein has a typical molten-globule structure at acidic pH when compared with pH 7.2. Human breast cells in cultu...Continue Reading

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Citations

Jun 21, 2012·The Journal of Biological Chemistry·Ana P D Ano BomJerson L Silva
Nov 16, 2012·PloS One·Danielly Cristiny Ferraz da CostaJerson L Silva
Jan 3, 2014·Biophysical Chemistry·Karen M GonçalvesYraima Cordeiro
Jul 18, 2014·Journal of Molecular Modeling·Yu WangLin-Fang Du
Apr 21, 2012·Journal of Pharmaceutical Sciences·Vasco FilipeWim Jiskoot
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Jul 19, 2018·Oncotarget·Danielly C Ferraz da CostaJerson L Silva
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Aug 24, 2016·Cold Spring Harbor Perspectives in Biology·Danielly C F CostaJerson L Silva
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Feb 15, 2021·The FEBS Journal·Kenzui Taniue, Nobuyoshi Akimitsu
Jun 25, 2021·Chemical Science·Elaine C PetronilhoJerson L Silva
Jun 3, 2014·Chemical Reviews·Jerson L SilvaDebora Foguel
Dec 21, 2017·Accounts of Chemical Research·Jerson L SilvaGuilherme A P de Oliveira
Oct 12, 2019·Biochemistry·Ambuja NavalkarSamir K Maji

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Methods Mentioned

BETA
protein folding
NMR
Fluorescence
Transfection
fluorescence spectroscopy
circular dichroism
gel filtration
nuclear magnetic resonance
transfections

Software Mentioned

NMRVIEW
NMRpipe

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