p53 function
p53 is a tumor suppressor protein encoded by the Trp53 gene. When cells are exposed to damaging conditions, such as DNA damage, Trp53 gene transcription is upregulated, resulting in overexpression of p53. The tumor suppressor protein can then go on to trigger a number of cellular responses to alleviate the stress condition, or in the case of irreparable damage induce apoptosis (Figure 1).
Figure 1: Depiction of p53 activity in a cell under stress. DNA damage is caused when the cell is exposed to UV light. Expression of p53 is upregulated, resulting in a high concentration of activated tetrameric p53 (PDB: 5LGY [12]). Phosphorylation [11], acetylation [12], and other post-translational modifications may activate p53. Once activated, p53 acts as a transcription factor that binds a palindromic consensus sequence 5′-RRRCWWGYYY-3′ (R = purine, W = A or T, Y = pyrimidine) [13]. Three examples of genes that might be targeted for transcription are shown, with their protein products and functions. Gadd45-alpha (PDB: 2KG4) can cellular stop replication and repair DNA [14]. p21 binds and renders inactive the proliferating cell nuclear antigen (PCNA), which is a sliding clamp that enhances the processivity of a number DNA polymerases (PDB: 1F16 ) [15]. The effect is of this binding is cell cycle arrest. The Bax protein is a promoter of apoptosis (PDB: 1F16 ) [16].
Structure of p53 tumor suppressor
The activated form of p53 is known to be a homotetramer. Each monomer has 392 amino acid residues, and several distinct domains of the protein have been characterized.
Transactivation domain
The first 92 residues of p53 are referred to as the transactivation domain. This region has a high degree of conformational flexibility and intrinsic disorder, which has historically made it difficult to characterize structurally. The domain contains a number of sites that bind proteins that activate, sequester, or deactivate p53 [11].
Core DNA-binding domain
The core DNA-binding domain is responsible for the key function of p53 as a tumor suppressor. From a number of crystallographic and solution NMR structural studies [12, 17, 18], it is known that a loop-helix-loop motif partially stabilized by zinc ion coordination mediates binding to the DNA (Figure 2). The specific residue contacts with the DNA vary depending on the post-translation modifications present on the activated p53; for example, when it is not acetylated Lys-120 has been found to be oriented toward the DNA phosphodiester backbone, but when acetylated the side chain will bury into the interior of the protein and form a close contact with an arginine residue [12].
Figure 2: (left) Tetrameric Lys120-acetylated core domain of the human p53 tumor suppressor in complex with the BAX response element (responsible for encoding the Bax apoptotic factor). Acetylated lysine residues shown as spheres. (right) Side view of a single p53 unit interacting with the same DNA fragment. A zinc ion can be seen (mauve) coordinated to several histidine and cysteine residues. Residues on the L1 loop and H1 helix interact closely with the DNA. Several cationic residues form close contacts with DNA phosphate groups (PDB: 5LGY) [12].
The description is very detailed, but the reader gets lost scrolling through the long paragraphs. A simple diagram which shows the interaction of P53 and MDM2 that the reader could reference as they read through the description would really help understanding.
Like Lucas said, this is a very detailed and well explained section. I was intrigued at the many functional domains of p53 as well as the cool regulatory feedback action of MDM2 protein. Since this is a lot of information, I do agree that a summary figure would be helpful to compile the information. This section contains important p53 structure-function information so the figure could also be organized in a way to summarize these structure-function relationships in its mode of action. Really impressed by this section!
As both Lucas and Suraj have said, the detail in this section is incredible . The figures are also very well done with fantastic captions.
It is a really interesting pathway, but I would love some mention of D-proteins on this page. You briefly touch upon how it will be useful at the end, but since this website is about mirror image proteins, keeping that theme running through every page would be helpful.
I know that you have a whole page dedicated to how this pathway and D-proteins relate. Maybe put a brief summary of it here or hyperlink to it.
To the tufts.edu webmaster, Thanks for the well-organized and comprehensive post!
Ten artykuł jest interesujący, ale na naszej stronie znajdziecie więcej informacji.