1. Structural Biology and Molecular Biophysics
  2. Cell Biology
Download icon

p53 Family Proteins: Damage limitation

  1. Ivano Amelio  Is a corresponding author
  2. Gerry Melino  Is a corresponding author
  1. Leicester University, United Kingdom
  2. University of Rome Tor Vergata, Italy
Insight
Cite this article as: eLife 2016;5:e17394 doi: 10.7554/eLife.17394
2 figures

Figures

Activation of TAp63α.

The process that causes inactive TAp63α dimers to become active TAp63α tetramers is triggered by phosphorylation (blue dots; blue plus sign). However, the precise role played by phosphorylation was not fully understood. The simplest assumption would be that the dimer is more stable than the tetramer (that is, the energy of the dimer state is lower than the energy of the tetramer state; top left), and that phosphorylation makes the tetramer more stable (bottom left). Under this assumption the activation process would be reversible and dephosphorylation (blue minus sign) would return the system to its original state (top left). However, experiments showed that the activation process was irreversible. Coutandin et al. show that the tetramer is considerably more stable than the dimer (top right), and that there is an energy barrier between the two. Phosphorylation triggers the spring-loaded mechanism that enables the system to overcome this barrier (bottom right). The large energy gap between the dimer and tetramer means that the system cannot return to the dimer state.

Activation of the different members of the p53 family of transcription factors.

TAp63α is a member of the p53 family of proteins, which also includes p53 and p73: these proteins are all transcription factors, so they need to be able to bind to DNA (bottom row). Some mutant forms of p53 can contribute to cancer phenotypes by binding to the C-terminal of normal p53 and p73 proteins: however, these mutant forms cannot bind to TAp63α dimers (because C-terminal regions of the dimers are not accessible). Phosphorylation (blue dots) is the trigger for activation of all three family members, but the mechanism is different for each. For p53 (left) phosphorylation mainly inhibits degradation by proteasomes, thus promoting stabilization of the protein; for TAp73α (right) phosphorylation affects the DNA binding affinity; and for TAp63α (middle) phosphorylation enables the opening up of dimers, which are inactive, in order to form tetramers, which are active. Acetylation (green dots) is also involved in the activation of p53 and TAp73α.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)