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Ann Taylor p53 sandbox: Difference between revisions

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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.
p53, also known as TP53 (for Tumor Protein 53) was named "Molecule of the Year" by Science Magazine for its important role in both cell cycle regulation and apoptosis().  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 is due tothe high number of proline residues in the protein, which causes it to migrate slowly on SDS-PAGE.<ref name="Ziemer MA, Mason A, Carlson DM (September 1982). Cell-free translations of proline-rich protein mRNAs. J. Biol. Chem. 257 (18): 11176–80.">[http://www.jbc.org/cgi/pmidlookup?view=long&pmid=7107651. Ziemer MA, Mason A, Carlson DM (September 1982). "Cell-free translations of proline-rich protein mRNAs". J. Biol. Chem. 257 (18): 11176–80. PMID 7107651.], </ref>


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


-Transcription activation domain
Human p53 is 393 amino acids long and has several domains:


-Activation domain 2
1.  The amino terminus (1-44) contains the transactivation domain which is responsible for activating downstream target genes.


-Proline rich domain
2.  A proline-rich domain (58-101) mediates the p53 response to DNA damage through apoptosis.


-DNA binding core domain
3.  A core DNA-binding domain (102-292), which is the target of 90% of p53 mutations found in human cancers.  A single mutation within this domain is sufficient to cause a major conformational change.


-A nuclear localization signaling domain
4.  An oligomerization domain (325-256), which contains a β-strand which interacts with another p53 monomer to form a dimer, followed by an α-helix which mediates the dimerization of two p53 dimers to form a tetramer.


-Tetramerizatin domain
5.  Two nuclear export signals (NES), found within the oligomerization domain, is rich in leucine residues and is highly conserved.  It is proposed that oligomerization masks the NES, resulting in p53 remaining in the nucleus.


-C-terminal domain()
6.  Three putative nuclear localization signals (NLS) in the C-terminus have been identified via mutagenesis and sequence similarity. 


p53 tumor suppressor is a
The intact p53 monomer is flexible and does not form orderly crystals. Consequently, the entire structure is not known.  Instead, segments have been isolated and characterized. The figure at the right shows the cartoon representation of DNA binding domain that has been studied most rigorously.
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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{{STRUCTURE_1tsr|  PDB=1tsr  |  SCENE='Ann_Taylor_p53_sandbox/P53_dna/1' }}


[[<scene name='Ann_Taylor_p53_sandbox/P53_dna/1'>p53 bound to DNA</scene>]]
<applet scene='Ann_Taylor_p53_sandbox/P53_dna/1' size='300' color='white' frame='true' align='right' caption='p53 bound to DNA' />  


'''p53 Pathway and mutation'''   
'''p53 Pathway and mutation'''   




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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  
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  
<scene name='Ann_Taylor_p53_sandbox/Arg_248/1'>R248</scene> 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.
<scene name='Ann_Taylor_p53_sandbox/Arg_248/1'>R248</scene> that interacts with DNA when mutated to another amino acid this interaction is lost. Other residues that are commonly mutated are arginine 175, 249, 273, 282 and glycine 245.  
 




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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 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.()
The figure at the left shows the surface charge of 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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<applet scene='Ann_Taylor_p53_sandbox/Zn_1/1' size='350' color='white' frame='true' align='right' caption='p53 bound to DNA' /> 


<applet load='1TUP' size='350' frame='true' align='right' caption='Insert caption here' />


<scene name='Ann_Taylor_p53_sandbox/P53_dna/1'>p</scene>


There is a Zn-binding motif on p53. The p53 Zn atom (shown in red) is coordinated by residues
<scene name='Ann_Taylor_p53_sandbox/Zn_binding/1'>C176, H179, C238, and C242</scene> that are located on two loops, respectively. It is conceivable that the
zinc plays a role of stabilizing two loops through
coordination().


There is a Zn-binding motif on p53. The p53 Zn atom is coordinated by residues
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C176, H179, C238, and C242 that are located on two loops, respectively. It is conceivable that the
{{Reflist}}
zinc plays a role of stabilizing two loops through
coordination(). The Zn has been represented as red sphere in the figure at the right.

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Ann Taylor
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