P53

p53 Tumor Suppressor Protein

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The name p53 refers to its 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 is actually 43.7 kDa. This difference may be due to the high number of proline residues in the protein, resulting in its migrating slowly on SDS-PAGE.

Human p53 is 393 amino acids long and has seven domains:

- Transcription activation domain (TAD)

- Activation domain 2

- Proline rich domain

- DNA-binding core domain (DBD)

- A nuclear localization signaling domain

- Tetramerizatin domain

- C-theminal 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 the DNA-binding domain, which has been studied most.

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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 is 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 damage is repaired. If the damage is irreparable, p53 initiates the process called programmed cell death, apoptosis, permanently removing the damage.

In most cases of human cancer, p53 mutations have been observed. Most of the p53 mutations that may result in cancer are found in and around the DNA-binding surface of the protein. The most common mutation changes R248, an amino acid that interacts with DNA. When mutated to another amino acid, this interaction is lost. Other residues associated with cancer-causing mutations are arginine 175, 249, 273, 282 and glycine 245. The figure at the right shows interaction of the DNA-binding domain with DNA. Key residues associated with mutations are represented by spheres.

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Surface charge of the DNA binding domain

The figure at the left shows the surface charge of the p53 DNA-binding domain. It is rich in arginine amino acids that interact with DNA, and this causes its surface to be positively charged. This domain recognizes specific regulatory sites on the DNA. The flexible structure of p53 allows it to bind to many different variants of binding sites, allowing it to regulate transcription at many places in the genome.

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spinqualitylabelsall models p53 DNA-binding domain complex with DNA and Zn+2 ions 1tup Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 in stabilizing the two loops through coordination. The Zn has been represented as a red sphere in the figure at the right.

3D structures of p533D structures of p53

p53 DNA-binding domainp53 DNA-binding domain

1ybg, 2xwr, 2ocj – h-p53 DBD – human
2fej - h-p53 DBD]] - NMR
2wgx, 3d05, 3d06, 3d07, 3d08, 3d09, 2qvq, 2qxa, 2qxb, 2qxc, 2pcx, 2j1w, 2j1x, 2j1y, 2j1z, 2j20, 2j21, 2bim, 2bin, 2bio, 2bip, 2biq, 1uol - h-p53 DBD (mutant)
1hs5 - h-p53 residues 324-357]] - NMR
2ioi, 2ioo, 1hu8 – m-p53 DBD – mouse
1t4w – p53-like DBD – Caenoharbditis elegans

p53 DNA-binding domain complex with DNAp53 DNA-binding domain complex with DNA

3igk, 3igl, 3kz8, 3kmd, 2ac0, 2ady, 2ahi, 2ata, 1tsr, 1tup – h-p53 DBD + DNA
3d0a - h-p53 DBD (mutant) + DNA
3exj, 3exl, 2p52, 2geq – m-p53 DBD + DNA

p53 DNA-binding domain complex with small moleculep53 DNA-binding domain complex with small molecule

2x0u, 2x0v, 2x0w – h-p53 DBD (mutant) + benzene derivative
2vuk - h-p53 DBD + drug
2iom - m-p53 DBD + propanol

p53 DNA-binding domain complex with protein
p53 DNA-binding domain complex with protein

2k8f – h-p53 residues 1-39 + histone acetyltransferase (mutant) – NMR
2h1l - h-p53 DBD + large T antigen
1ycs - h-p53 DBD + 53BP2
1gzh, 1kzy - h-p53 DBD + tumor suppressor p53-binding protein

p53 transactivation domainp53 transactivation domain

2z5s, 2z5t - h-p53 TAD + MDM4 protein
1ycq, 1ycr - h-p53 TAD + MDM2 protein
2l14 – h-p53 TAD + CREB-binding protein
2gs0 – h-p53 TAD + RNA polymerase II transcription factor

p53 oligomerization domainp53 oligomerization domain

2j0z, 3sak, 1sae, 1saf, 1sah, 1saj, 1sak, 1sal, 1olh, 1pes, 1pet, 1olg – h-p53 tetramerization domain – NMR
1c26, 1aie - h-p53 tetramerization domain
2j10, 2j11, 1a1u - h-p53 tetramerization domain (mutant) – NMR

Additional ResourcesAdditional Resources

For additional information, see: Cancer
For additional information, see: Oncogenes