P53: Difference between revisions
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p53 Tumor Suppressor | p53 Tumor Suppressor | ||
[[Image:p53-unbound.gif|right | [[Image:p53-unbound.gif|right]] | ||
==Guardian of the Cell== | ==Guardian of the Cell== | ||
Our cells face many dangers, including chemicals, viruses, and ionizing radiation. If cells are damaged in sensitive places by these attackers, the effects can be disastrous. For instance, if key regulatory elements are damaged, the normal controls on cell growth may be blocked and the cell will rapidly multiply and grow into a tumor. p53 tumor suppressor is one of our defenses against this type of damage. p53 tumor suppressor is normally found at low levels, but when DNA damage is sensed, p53 levels rise and initiate protective measures. p53 binds to many regulatory sites in the genome and begins production of proteins that halt cell division until the damage is repaired. Or, if the damage is too severe, p53 initiates the process of programmed cell death, or apoptosis, which directs the cell to commit suicide, permanently removing the damage. | Our cells face many dangers, including chemicals, viruses, and ionizing radiation. If cells are damaged in sensitive places by these attackers, the effects can be disastrous. For instance, if key regulatory elements are damaged, the normal controls on cell growth may be blocked and the cell will rapidly multiply and grow into a tumor. p53 tumor suppressor is one of our defenses against this type of damage. p53 tumor suppressor is normally found at low levels, but when DNA damage is sensed, p53 levels rise and initiate protective measures. p53 binds to many regulatory sites in the genome and begins production of proteins that halt cell division until the damage is repaired. Or, if the damage is too severe, p53 initiates the process of programmed cell death, or apoptosis, which directs the cell to commit suicide, permanently removing the damage. | ||
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==Embracing DNA== | ==Embracing DNA== | ||
[[Image:p53-bound.gif|right | [[Image:p53-bound.gif|right]] | ||
p53 tumor suppressor binds to DNA using all four of its arms. The typical binding site for the whole molecule is composed of three parts: a specific binding site for two p53 domains, a variable stretch of 0 to 13 base pairs, and a second specific binding site for the other two p53 domains. In the picture shown here (constructed from PDB entries [[1tup]], [[1olg]] and [[1ycq]]), two p53 domains are bound near the top of the DNA strand and two are bound at an identical site near the bottom. The tetramerization domain is behind the helix, tying all four chains together, and the four transactivation domains extend along the DNA helix, ready to activate neighboring proteins involved in reading the DNA. The flexible chains that connect all four arms together allow p53 to bind to many different variants of this binding site, allowing it to regulate transcription at many places in the genome. | p53 tumor suppressor binds to DNA using all four of its arms. The typical binding site for the whole molecule is composed of three parts: a specific binding site for two p53 domains, a variable stretch of 0 to 13 base pairs, and a second specific binding site for the other two p53 domains. In the picture shown here (constructed from PDB entries [[1tup]], [[1olg]] and [[1ycq]]), two p53 domains are bound near the top of the DNA strand and two are bound at an identical site near the bottom. The tetramerization domain is behind the helix, tying all four chains together, and the four transactivation domains extend along the DNA helix, ready to activate neighboring proteins involved in reading the DNA. The flexible chains that connect all four arms together allow p53 to bind to many different variants of this binding site, allowing it to regulate transcription at many places in the genome. | ||
==Exploring the Structure== | ==Exploring the Structure== | ||
[[Image:p53-mutations.gif|right | [[Image:p53-mutations.gif|right]] | ||
Most of the p53 mutations that cause cancer are found in the DNA-binding domain. The most common mutations are shown here, using PDB entry 1tup. This PDB entry includes three copies of the DNA-binding domain; only one (chain B in the file) is shown here. The mutations are found in and around the DNA-binding face of the protein. The most common mutation changes arginine 248, colored red here. Notice how it snakes into the minor groove of the DNA (shown in blue and green), forming a strong stabilizing interaction. When mutated to another amino acid, this interaction is lost. Other key sites of mutation are shown in pink, including arginine residues 175, 249, 273 and 282, and glycine 245. Some of these contact the DNA directly, and others are involved in positioning other DNA-binding amino acids. | Most of the p53 mutations that cause cancer are found in the DNA-binding domain. The most common mutations are shown here, using PDB entry 1tup. This PDB entry includes three copies of the DNA-binding domain; only one (chain B in the file) is shown here. The mutations are found in and around the DNA-binding face of the protein. The most common mutation changes arginine 248, colored red here. Notice how it snakes into the minor groove of the DNA (shown in blue and green), forming a strong stabilizing interaction. When mutated to another amino acid, this interaction is lost. Other key sites of mutation are shown in pink, including arginine residues 175, 249, 273 and 282, and glycine 245. Some of these contact the DNA directly, and others are involved in positioning other DNA-binding amino acids. | ||
