P53-DNA Recognition: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Jaime Prilusky, Remo Rohs, Bailey Holmes, Ana Carolina Dantas Machado, Eran Hodis, Julia Tam, Masha Karelina, Sharon Kim, Skyler Saleebyan, Keziah Kim, Joseph M. Steinberger, Eric Martz, Alexander Berchansky, Michal Harel, Angel Herraez, Joel L. Sussman

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 [[Image:p53-domains.jpg|thumb|right|400px|Figure 3:  Frequency of p53 mutants associated with cancer derived from [http://www-p53.iarc.fr/ IARC TP53 database]. Domain architecture; N-ter=N-terminal, DBD=DNA binding domain<ref name='kitayner'/>, Tet=Tetramerization<ref name='tetra'>Jeffrey PD, Gorina S, Pavletich NP. Crystal structure of the p53 tetramerization domain. Science 1995;267:1498-502.</ref>, and C-ter=C-terminal domain. Intermediate regions are fairly disordered.]]
-Also known as the '''Guardian of the Genome''', the tumor suppressor p53 is crucial in the natural defense against human cancer. The protein is activated by stress factors that can compromise the genomic integrity of the cell, and this activation unleashes the function of p53 as a transcription factor. It binds as a tetramer (Figure 1) to a large range of DNA response elements. The p53 consensus site  (Figure 2) is formed by two decameric half-sites, each containing a core element (red), that are separated by a variable number of base pairs (blue).
+Also known as the '''Guardian of the Genome''', the tumor suppressor p53 is crucial in the natural defense against human cancer. The protein is activated by stress factors that can compromise the genomic integrity of the cell. This activation unleashes the function of p53 as a transcription factor. It binds as a tetramer (Figure 1) to a large range of DNA response elements. The p53 consensus site  (Figure 2) is formed by two decameric half-sites, each containing a core element (red), that are separated by a variable number of base pairs (blue).
 Binding of p53 to different response elements leads to distinct biological responses, such as cell-cycle arrest, senescence, or apoptosis. These different pathways correspond, at least in part, to differences in p53-DNA binding affinity and stability, which are determined by specific protein-DNA interactions.
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 <Structure load='P53tetra.pdb.zip' size='250' frame='true' align='left' caption='Figure 4: Crystal structure of p53 tetramerization domain, [http://proteopedia.com/wiki/index.php/1c26 PDB ID 1C26].' scene='Sandbox_Reserved_170/Tetra/2' />
-The p53 protein consists of the N-terminal transactivation, the DNA binding or core, the tetramerization, and the C-terminal regulatory domain (Figure 3). This Proteopedia page discusses protein-DNA recognition by p53, thus focuses on the DBD of p53. The only other domain for which structural information is available is the <scene name='Sandbox_Reserved_170/Tetra/2'>tetramerization domain</scene>, which forms as a dimer of dimers with one alpha helix and one beta strand contributed by each p53 monomer.
+The p53 protein consists of the N-terminal transactivation, the DNA binding or core, the tetramerization, and the C-terminal regulatory domain (Figure 3). This Proteopedia page discusses protein-DNA recognition by p53, thus focusing on the DBD of p53. The only other domain for which structural information is available is the <scene name='Sandbox_Reserved_170/Tetra/2'>tetramerization domain</scene>, which forms as a dimer of dimers with one alpha helix and one beta strand contributed by each p53 monomer.
 <Structure load='3kz8bio-4mon.pdb.zip' size='500' frame='true' align='right' caption='Figure 5: Crystal structure of p53 DBD tetramer-DNA complex, [http://proteopedia.com/wiki/index.php/3kz8 PDB ID 3KZ8.]' scene='Sandbox_Reserved_170/Complex/6' />
-The <scene name='Sandbox_Reserved_170/Complex/6'>DBD in tetrameric form binds to a response element</scene>, which consists of two half sites. These decameric half sites can be separated by a spacer of flexible length but in this case the spacer is of length zero base pairs. The <scene name='Sandbox_Reserved_170/Complex/7'>p53 tetramer binds DNA as a dimer of dimers</scene> with each dimer binding to one half site of the response element.
+The <scene name='Sandbox_Reserved_170/Complex/6'>DBD in tetrameric form binds to a response element</scene>, which consists of two half sites. These decameric half sites can be separated by a spacer of flexible length but in this case, the spacer is of length zero base pairs. The <scene name='Sandbox_Reserved_170/Complex/7'>p53 tetramer binds DNA as a dimer of dimers</scene> with each dimer binding to one half site of the response element.
 The p53 DBD assumes the conformation of an <scene name='Sandbox_Reserved_170/Beta/1'>immunoglobulin-like fold consisting of a beta sandwich</scene>, which binds the response element in the major groove. A functionally important <scene name='Sandbox_Reserved_170/Zn/1'>Zn2+ ion coordinates the Cys176, His179, Cys238, Cys242 residues</scene> and, thus, stabilizes the fold of the DBD.
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 Protein side chains and base pairs form direct contacts in the major groove. Among which, the <scene name='Sandbox_Reserved_170/Arg280_contact/5'>contact between Arg280 and the guanine of the core element</scene> contributes most to binding specificity. This highly specific readout is due to the <scene name='Sandbox_Reserved_170/Arg280_contact/4'>bidentate hydrogen bond formed between Arg280 and guanine</scene>. As a result of this '''base readout''' the G/C base pairs in the CWWG core elements are the most conserved positions in p53 response elements (Figure 6).
-Another important contact is formed with the <scene name='Sandbox_Reserved_170/Lys_120/3'>Lys120 residue from the L1 loop of the protein</scene>. Lys120 is biologically very important because acetylation of this residue is known to trigger the apoptotic response of p53.
+Another important contact is formed with the <scene name='Sandbox_Reserved_170/Lys_120/3'>Lys120 residue from the L1 loop of the protein</scene>. Lys120 is very important biologically because acetylation of this residue is known to trigger the apoptotic response of p53.
 ===DNA Backbone Contact===