scholarly journals Long-Range Modulation of Chain Motions within the Intrinsically Disordered Transactivation Domain of Tumor Suppressor p53

2012 ◽  
Vol 134 (3) ◽  
pp. 1617-1622 ◽  
Author(s):  
Jenifer K. Lum ◽  
Hannes Neuweiler ◽  
Alan R. Fersht
Keyword(s):  
Tumor Suppressor ◽  
Long Range ◽  
Transactivation Domain ◽  
Tumor Suppressor P53 ◽  
Intrinsically Disordered

scholarly journals Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain

2008 ◽  
Vol 105 (15) ◽  
pp. 5762-5767 ◽  
Author(s):  
M. Wells ◽  
H. Tidow ◽  
T. J. Rutherford ◽  
P. Markwick ◽  
M. R. Jensen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Transactivation Domain ◽  
Tumor Suppressor P53 ◽  
Intrinsically Disordered

scholarly journals Bridging microscopic and macroscopic mechanisms of p53-MDM2 binding using molecular simulations and kinetic network models

2016 ◽  
Author(s):  
Guangfeng Zhou ◽  
George A. Pantelopulos ◽  
Sudipto Mukherjee ◽  
Vincent A. Voelz
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Network Models ◽  
Tumor Suppressor Protein ◽  
Transactivation Domain ◽  
Trajectory Data ◽  
Tumor Suppressor Protein P53 ◽  
Intrinsically Disordered ◽  
Protein P53 ◽  
Good Agreement

Under normal cellular conditions, the tumor suppressor protein p53 is kept at a low levels in part due to ubiquitination by MDM2, a process initiated by binding of MDM2 to the intrinsically disordered transactivation domain (TAD) of p53. Although many experimental and simulation studies suggest that disordered domains such as p53 TAD bind their targets nonspecifically before folding to a tightly-associated conformation, the molecular details are unclear. Toward a detailed prediction of binding mechanism, pathways and rates, we have performed large-scale unbiased all-atom simulations of p53-MDM2 binding. Markov State Models (MSMs) constructed from the trajectory data predict p53 TAD peptide binding pathways and on-rates in good agreement with experiment. The MSM reveals that two key bound intermediates, each with a non-native arrangement of hydrophobic residues in the MDM2 binding cleft, control the overall on-rate. Using microscopic rate information from the MSM, we parameterize a simple four-state kinetic model to (1) determine that induced-fit pathways dominate the binding flux over a large range of concentrations, and (2) predict how modulation of residual p53 helicity affects binding, in good agreement with experiment. These results suggest new ways in which microscopic models of bound-state ensembles can be used to understand biological function on a macroscopic scale.AUTHOR SUMMARYMany cell signaling pathways involve protein-protein interactions in which an intrinsically disordered peptide folds upon binding its target. Determining the molecular mechanisms that control these binding rates is important for understanding how such systems are regulated. In this paper, we show how extensive all-atom simulations combined with kinetic network models provide a detailed mechanistic understanding of how tumor suppressor protein p53 binds to MDM2, an important target of new cancer therapeutics. A simple four-state model parameterized from the simulations shows a binding-then-folding mechanism, and recapitulates experiments in which residual helicity boosts binding. This work goes beyond previous simulations of small-molecule binding, to achieve pathways and binding rates for a large peptide, in good agreement with experiment.

Chemical Synthesis of the Multiply Phosphorylated and Biotinylated N-Terminal Transactivation Domain of Human p53 (p53TAD)

Synlett ◽  
2017 ◽  
Vol 28 (15) ◽  
pp. 1917-1922 ◽  
Author(s):  
Zhongping Tan ◽  
Xiaoyang Guan ◽  
Patrick Chaffey ◽  
Yuan Ruan ◽  
Connor Hurd ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Chemical Synthesis ◽  
Native Chemical Ligation ◽  
Methionine Oxidation ◽  
Phosphorylation Sites ◽  
Transactivation Domain ◽  
Biological Functions ◽  
Tumor Suppressor P53 ◽  
Chemical Ligation ◽  
Metal Free

Phosphorylation of the N-terminal transactivation domain (TAD) of tumor suppressor p53 (p53TAD) helps regulate many of p53’s biological functions. Chemical synthesis of the p53TAD sequence with various phosphorylation patterns, through native chemical ligation and metal-free desulfurization, would facilitate studies of p53TAD phosphorylation and its role in regulating p53 function. Here, unphosphorylated, mono- and pentaphosphorylated p53TAD constructs were chemically synthesized. During the synthesis, methionine oxidation was found to be a serious problem and reduction was required at different stages, according to the number of phosphorylation sites.

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