P53: Difference between revisions
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The name p53 | 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 | Human p53 is 393 amino acids long and has seven domains: | ||
-Transcription activation domain | - Transcription activation domain | ||
-Activation domain 2 | - Activation domain 2 | ||
-Proline rich domain | - Proline rich domain | ||
-DNA binding core domain | - DNA-binding core domain | ||
-A nuclear localization signaling domain | - A nuclear localization signaling domain | ||
-Tetramerizatin domain | - Tetramerizatin domain | ||
-C-theminal domain | - C-theminal domain | ||
p53 tumor suppressor is a | p53 tumor suppressor is a | ||
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to study by x-ray | to study by x-ray | ||
crystallography because they do | crystallography because they do | ||
not form orderly crystals. So | not form orderly crystals. So p53 has been | ||
studied in parts, by removing | studied in parts, by removing | ||
the flexible regions and solving | the flexible regions and solving | ||
structures of the pieces that | structures of the pieces that | ||
form stable structures. | form stable structures. | ||
The figure at the right shows the cartoon representation of DNA binding domain | The figure at the right shows the cartoon representation of the DNA-binding domain, which has been studied most. | ||
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[[Image:P53_DNA.png | 400 px | thumb]] | [[Image:P53_DNA.png | 400 px | thumb]] | ||
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In a normal cell p53 is inactivated by its negative regulatory mdm2 (hdm2 in humans) and it is found at low levels. | 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 of | In most cases of 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 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''' | '''Surface charge of the DNA binding domain''' | ||
The figure at the left shows the surface charge | 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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<applet load='1TUP' size='350' frame='true' align='right' caption='Insert caption here' /> | <applet load='1TUP' size='350' frame='true' align='right' caption='Insert caption here' /> | ||
<scene name='Sandbox/P53_dna_binding_domain/1'>Three | <scene name='Sandbox/P53_dna_binding_domain/1'>Three dimensional representation of the DNA-binding domain with DNA</scene> | ||
There is a Zn-binding motif on p53. The p53 Zn atom is coordinated by residues | 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 | C176, H179, C238, and C242 that are located on two loops, respectively. It is conceivable that the | ||
zinc plays a role | zinc plays a role in stabilizing the two loops through | ||
coordination | coordination. The Zn has been represented a as red sphere in the figure at the right. | ||
Revision as of 19:14, 6 September 2010
p53 Tumor Suppressor Protein
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
- Activation domain 2
- Proline rich domain
- DNA-binding core domain
- 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.
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 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 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.
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.
|
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 a as red sphere in the figure at the right.