Ann Taylor p53 sandbox
p53 Tumor Suppressor Protein
The name p53 reference to it apparent molecular mass. It runs as a 53 kDa molecule on SDS-PAGE. But based on calculations from its amino acid residues, p53's mass actually 43.7 kDa. This difference because of the high number of proline residues in the protein that migrates slowly on SDS-PAGE.
Human p53 is 393 amino acids long and has seven domains.
-Transcription activation domain
-Activation domain 2
-Proline rich domain
-DNA binding core domain
-A nuclear localization signaling domain
-Tetramerizatin domain
-C-terminal domain()
p53 tumor suppressor is a flexible molecule composed of four identical protein chains. Flexible molecules are difficult to study by x-ray crystallography because they do not form orderly crystals. So, p53 has been studied in parts, by removing the flexible regions and solving structures of the pieces that form stable structures.() The figure at the right shows the cartoon representation of DNA binding domain that has been studied most rigorously.
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p53 Pathway and mutation
In a normal cell p53 is inactivated by its negative regulatory mdm2 (hdm2 in humans) and it is found at low levels. When DNA damage sensed p53's level rises(). p53 binds to many regulatory sites in the genome and begins production of proteins that stop cell division until the demage is repaired, or if the damage is unrepairable, p53 initiates the process programmed cell death,also known as apoptosis, permanently removing the damaged cell.()
In most of the human cancer p53 mutations has been observed. Most of the p53 mutations that cause cancer are found in and around the DNA binding surface of the protein.The most common mutation changes
that interacts with DNA when mutated to another amino acid this interaction is lost. Other residues that goes mutations are arginine 175, 249, 273, 282 and glycine 245. The figure at the right shows interaction of DNA binding domain with DNA and key residues in mutations are represented by spheres.
Surface charge of the DNA binding domain
The figure at the left shows the surface charge og the p53 DNA binding domain. It is rich in arginine amino acids to interact with DNA, thus this cause its surface positively charged. This domain recognizes specific regulatory sites on the DNA and flexible structure of p53 allow it to bind to many different variant of binding site allowing it to regulate transcription at many places in the genome.()
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There is a Zn-binding motif on p53. The p53 Zn atom is coordinated by residues
C176, H179, C238, and C242 that are located on two loops, respectively. It is conceivable that the
zinc plays a role of stabilizing two loops through
coordination(). The Zn has been represented as red sphere in the figure at the right.