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Evidence for allosteric effects on p53 oligomerization induced by phosphorylation
P. Muller, JM. Chan, O. Simoncik, M. Fojta, DP. Lane, T. Hupp, B. Vojtesek,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Free Medical Journals
od 1992 do Před 1 rokem
PubMed Central
od 1992 do Před 1 rokem
Europe PubMed Central
od 1992 do Před 1 rokem
Medline Complete (EBSCOhost)
od 2010-01-01 do Před 1 rokem
Wiley Free Content
od 1996 do Před 1 rokem
PubMed
29124793
DOI
10.1002/pro.3344
Knihovny.cz E-zdroje
- MeSH
- adenosintrifosfát metabolismus MeSH
- alosterická regulace MeSH
- fosforylace MeSH
- kaseinkinasa II metabolismus MeSH
- lidé MeSH
- molekulární modely MeSH
- multimerizace proteinu MeSH
- mutace MeSH
- nádorový supresorový protein p53 chemie genetika metabolismus MeSH
- proteinové domény MeSH
- stabilita proteinů MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
p53 is a tetrameric protein with a thermodynamically unstable deoxyribonucleic acid (DNA)-binding domain flanked by intrinsically disordered regulatory domains that control its activity. The unstable and disordered segments of p53 allow high flexibility as it interacts with binding partners and permits a rapid on/off switch to control its function. The p53 tetramer can exist in multiple conformational states, any of which can be stabilized by a particular modification. Here, we apply the allostery model to p53 to ask whether evidence can be found that the "activating" C-terminal phosphorylation of p53 stabilizes a specific conformation of the protein in the absence of DNA. We take advantage of monoclonal antibodies for p53 that measure indirectly the following conformations: unfolded, folded, and tetrameric. A double antibody capture enzyme linked-immunosorbent assay was used to observe evidence of conformational changes of human p53 upon phosphorylation by casein kinase 2 in vitro. It was demonstrated that oligomerization and stabilization of p53 wild-type conformation results in differential exposure of conformational epitopes PAb1620, PAb240, and DO12 that indicates a reduction in the "unfolded" conformation and increases in the folded conformation coincide with increases in its oligomerization state. These data highlight that the oligomeric conformation of p53 can be stabilized by an activating enzyme and further highlight the utility of the allostery model when applied to understanding the regulation of unstable and intrinsically disordered proteins.
Institute of Biophysics Academy of Sciences of the Czech Republic Brno 612 65 Czech Republic
p53 Laboratory Singapore 138648 Singapore
RECAMO Masaryk Memorial Cancer Institute Brno 65653 Czech Republic
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- $a p53 is a tetrameric protein with a thermodynamically unstable deoxyribonucleic acid (DNA)-binding domain flanked by intrinsically disordered regulatory domains that control its activity. The unstable and disordered segments of p53 allow high flexibility as it interacts with binding partners and permits a rapid on/off switch to control its function. The p53 tetramer can exist in multiple conformational states, any of which can be stabilized by a particular modification. Here, we apply the allostery model to p53 to ask whether evidence can be found that the "activating" C-terminal phosphorylation of p53 stabilizes a specific conformation of the protein in the absence of DNA. We take advantage of monoclonal antibodies for p53 that measure indirectly the following conformations: unfolded, folded, and tetrameric. A double antibody capture enzyme linked-immunosorbent assay was used to observe evidence of conformational changes of human p53 upon phosphorylation by casein kinase 2 in vitro. It was demonstrated that oligomerization and stabilization of p53 wild-type conformation results in differential exposure of conformational epitopes PAb1620, PAb240, and DO12 that indicates a reduction in the "unfolded" conformation and increases in the folded conformation coincide with increases in its oligomerization state. These data highlight that the oligomeric conformation of p53 can be stabilized by an activating enzyme and further highlight the utility of the allostery model when applied to understanding the regulation of unstable and intrinsically disordered proteins.
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