Aggregation-primed molten globule conformers of the p53 core domain provide potential tools for studying p53C aggregation in cancer.

The Journal of Biological Chemistry
Murilo M PedroteJerson L Silva

Abstract

The functionality of the tumor suppressor p53 is altered in more than 50% of human cancers, and many individuals with cancer exhibit amyloid-like buildups of aggregated p53. An understanding of what triggers the pathogenic amyloid conversion of p53 is required for the further development of cancer therapies. Here, perturbation of the p53 core domain (p53C) with subdenaturing concentrations of guanidine hydrochloride and high hydrostatic pressure revealed native-like molten globule (MG) states, a subset of which were highly prone to amyloidogenic aggregation. We found that MG conformers of p53C, probably representing population-weighted averages of multiple states, have different volumetric properties, as determined by pressure perturbation and size-exclusion chromatography. We also found that they bind the fluorescent dye 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) and have a native-like tertiary structure that occludes the single Trp residue in p53. Fluorescence experiments revealed conformational changes of the single Trp and Tyr residues before p53 unfolding and the presence of MG conformers, some of which were highly prone to aggregation. p53C exhibited marginal unfolding cooperativity, which could be modu...Continue Reading

References

Jan 1, 1991·European Biophysics Journal : EBJ·H Christensen, R H Pain
Jul 17, 2001·Journal of Agricultural and Food Chemistry·J YangB G Swanson
Jan 10, 2002·Proceedings of the National Academy of Sciences of the United States of America·Assaf FriedlerAlan R Fersht
Nov 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Natalia IssaevaGalina Selivanova
Feb 8, 2006·Proceedings of the National Academy of Sciences of the United States of America·José Manuel Pérez CañadillasAlan R Fersht
May 11, 2006·Chemical Reviews·Catherine A Royer
Jun 27, 2006·Nature·Mourad SadqiVictor Muñoz
Jan 11, 2007·The Journal of Biological Chemistry·Remo GerberWilliam James
Jan 4, 2008·Proceedings of the National Academy of Sciences of the United States of America·Samuel S ChoPeter G Wolynes
Jun 10, 2009·Biochemistry·Daniella IshimaruJerson L Silva
Jul 21, 2009·Proceedings of the National Academy of Sciences of the United States of America·Santosh Kumar Jha, Jayant B Udgaonkar
Aug 28, 2009·The Journal of Physical Chemistry. B·Atanu Das, Chaitali Mukhopadhyay
Nov 26, 2009·The Journal of Biological Chemistry·Ana Paula D Ano BomJerson L Silva
Mar 3, 2010·Proceedings of the National Academy of Sciences of the United States of America·Andreas ReinerThomas Kiefhaber
Jun 23, 2010·Journal of the American Chemical Society·Lukasz SkoraMarkus Zweckstetter
Jul 17, 2010·Proteins·Robert L BaldwinGeorge D Rose
Nov 9, 2010·The International Journal of Biochemistry & Cell Biology·Claudia B LevyClaudia V De Moura-Gallo
Nov 17, 2010·Analytical Biochemistry·Nicholas G JamesDavid M Jameson
Jan 21, 2011·The Journal of Physical Chemistry. B·Ruhong ZhouB J Berne
Apr 13, 2012·Proceedings of the National Academy of Sciences of the United States of America·Julien RocheCatherine A Royer
Jun 21, 2012·The Journal of Biological Chemistry·Ana P D Ano BomJerson L Silva
Aug 25, 2012·Journal of Molecular Biology·Peter CanningAlex N Bullock
Dec 15, 2012·Current Opinion in Structural Biology·Robert L Baldwin, George D Rose
Mar 19, 2014·Proceedings of the National Academy of Sciences of the United States of America·Santosh Kumar Jha, Susan Marqusee
May 6, 2014·Journal of Molecular Biology·Sabine Neumaier, Thomas Kiefhaber
Jun 3, 2014·Chemical Reviews·Jerson L SilvaDebora Foguel
Feb 13, 2015·Proceedings of the National Academy of Sciences of the United States of America·GuoZhen Wang, Alan R Fersht
May 13, 2015·Proceedings of the National Academy of Sciences of the United States of America·Guilherme A P de Oliveira, Jerson L Silva
Dec 25, 2015·The Journal of Physical Chemistry Letters·Nirbhik AcharyaSantosh Kumar Jha
Feb 5, 2016·Current Opinion in Structural Biology·Victor MuñozMourad Sadqi
Apr 28, 2016·Journal of the American Chemical Society·Theodoros K KaramanosSheena E Radford
May 27, 2016·Scientific Reports·Andreas EnthartFranz Hagn
Aug 24, 2016·Cold Spring Harbor Perspectives in Biology·Danielly C F CostaJerson L Silva
Sep 8, 2016·Scientific Reports·Elio A CinoJerson L Silva
Mar 16, 2017·Proceedings of the National Academy of Sciences of the United States of America·GuoZhen Wang, Alan R Fersht
Apr 6, 2017·Biophysical Chemistry·Guilherme A P de Oliveira, Jerson L Silva
Apr 20, 2017·The Journal of Biological Chemistry·Petar Stefanov KovachevSuparna Sanyal

❮ Previous
Next ❯

Citations

Apr 28, 2019·The Journal of Biological Chemistry·Nataly Melo Dos SantosEtel Rodrigues Pereira Gimba
Apr 9, 2020·Biomolecules·Guilherme A P de OliveiraJerson L Silva
Jun 10, 2019·The FEBS Journal·Andrea M ClarkSteven M Pascal
Apr 21, 2020·Physical Chemistry Chemical Physics : PCCP·Le LiGuanghong Wei
Jun 25, 2021·Chemical Science·Elaine C PetronilhoJerson L Silva
Oct 12, 2019·Biochemistry·Ambuja NavalkarSamir K Maji
Oct 7, 2021·Physical Chemistry Chemical Physics : PCCP·Jiangtao LeiXiaohua Deng
Jul 28, 2020·Biochimica Et Biophysica Acta. Biomembranes·Luis Benito Pérez Socas, Ernesto Esteban Ambroggio

❮ Previous
Next ❯

Methods Mentioned

BETA
light scattering
NMR
protein folding
size-exclusion chromatography
gel filtration

Software Mentioned

Mathematica

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.