Sandbox Reserved 654: Difference between revisions

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Until recently, the function of the bromodomain remained unknown. Its structure and modularity, along with its feature of both N and C termini located together on one end of the protein, suggested that it played a role in protein-protein interactions. It has now been shown that the hydrophobic pocket formed by the loops is the primary binding site for acetyl-lysine proteins, making the bromodomain a functional site for recognition of acetylated lysine residues playing a role in regulation via protein-protein interactions<ref name=a/>. This interaction has been shown via localization and chemical shift experiments that revealed the specific manner with which the bromodomain hydrophobic cavity binds to acetylated lysine residues.

Once the acetyl-lysine residue makes the initial binding inside the hydrophobic pocket, the ZA and BC loop residues at the entrance of the pocket interact with the amino acids adjacent (+/- 1 or 2) to the already bound acetyl-lysine. Those interactions reinforce binding of the target sequence<ref>Mujtaba, S. et al (2007) Oncogene 26, 5521 [http://www.nature.com/onc/journal/v26/n37/abs/1210618a.html]. Small structural changes in the conformation of the ZA and BC loops result in exposing other residues that are originally buried within the protein to aid in peptide recognition<ref name=b> Mujtaba, S. et al (2002) Mol. Cell 9, 575 [http://www.cell.com/molecular-cell/retrieve/pii/S1097276502004835]</ref>.

Once the acetyl-lysine residue makes the initial binding inside the hydrophobic pocket, the ZA and BC loop residues at the entrance of the pocket interact with the amino acids adjacent (+/- 1 or 2) to the already bound acetyl-lysine. Those interactions reinforce binding of the target sequence<ref>Mujtaba, S. et al (2007) Oncogene 26, 5521 [http://www.nature.com/onc/journal/v26/n37/abs/1210618a.html]. Small structural changes in the conformation of the ZA and BC loops result in exposing other residues that are originally buried within the protein to aid in peptide recognition<ref name=f> Mujtaba, S. et al (2002) Mol. Cell 9, 575 [http://www.cell.com/molecular-cell/retrieve/pii/S1097276502004835]</ref>.

It is also believed that the bromodomain may also play a role in highly specific histone acetylation by tethering transcriptional HATs to specific chromosomal sites<ref> Brownell, J. et al (1996) Curr. Opin. Genet. Dev. 6, 176 [http://www.sciencedirect.com/science/article/pii/S0959437X96800487]<ref/> as well as the assembly of multiprotein complexes in transcriptional activation such as the Bromodomain–HIV-1 Tat complex necessary for HIV-1 transcriptional activation<ref name=b/>.

It is also believed that the bromodomain may also play a role in highly specific histone acetylation by tethering transcriptional HATs to specific chromosomal sites<ref> Brownell, J. et al (1996) Curr. Opin. Genet. Dev. 6, 176 [http://www.sciencedirect.com/science/article/pii/S0959437X96800487]<ref/> as well as the assembly of multiprotein complexes in transcriptional activation such as the Bromodomain–HIV-1 Tat complex necessary for HIV-1 transcriptional activation<ref name=f/>.

== '''Mechanism''' ==

Sandbox Reserved 654: Difference between revisions

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 Until recently, the function of the bromodomain remained unknown. Its structure and modularity, along with its feature of both N and C termini located together on one end of the protein, suggested that it played a role in protein-protein interactions. It has now been shown that the hydrophobic pocket formed by the loops is the primary binding site for acetyl-lysine proteins, making the bromodomain a functional site for recognition of acetylated lysine residues playing a role in regulation via protein-protein interactions<ref name=a/>. This interaction has been shown via localization and chemical shift experiments that revealed the specific manner with which the bromodomain hydrophobic cavity binds to acetylated lysine residues.
-Once the acetyl-lysine residue makes the initial binding inside the hydrophobic pocket, the ZA and BC loop residues at the entrance of the pocket interact with the amino acids adjacent (+/- 1 or 2) to the already bound acetyl-lysine. Those interactions reinforce binding of the target sequence<ref>Mujtaba, S. et al (2007) Oncogene 26, 5521 [http://www.nature.com/onc/journal/v26/n37/abs/1210618a.html]. Small structural changes in the conformation of the ZA and BC loops result in exposing other residues that are originally buried within the protein to aid in peptide recognition<ref name=b> Mujtaba, S. et al (2002) Mol. Cell 9, 575 [http://www.cell.com/molecular-cell/retrieve/pii/S1097276502004835]</ref>.
+Once the acetyl-lysine residue makes the initial binding inside the hydrophobic pocket, the ZA and BC loop residues at the entrance of the pocket interact with the amino acids adjacent (+/- 1 or 2) to the already bound acetyl-lysine. Those interactions reinforce binding of the target sequence<ref>Mujtaba, S. et al (2007) Oncogene 26, 5521 [http://www.nature.com/onc/journal/v26/n37/abs/1210618a.html]. Small structural changes in the conformation of the ZA and BC loops result in exposing other residues that are originally buried within the protein to aid in peptide recognition<ref name=f> Mujtaba, S. et al (2002) Mol. Cell 9, 575 [http://www.cell.com/molecular-cell/retrieve/pii/S1097276502004835]</ref>.
-It is also believed that the bromodomain may also play a role in highly specific histone acetylation by tethering transcriptional HATs to specific chromosomal sites<ref> Brownell, J. et al (1996) Curr. Opin. Genet. Dev. 6, 176 [http://www.sciencedirect.com/science/article/pii/S0959437X96800487]<ref/> as well as the assembly of multiprotein complexes in transcriptional activation such as the Bromodomain–HIV-1 Tat complex necessary for HIV-1 transcriptional activation<ref name=b/>.
+It is also believed that the bromodomain may also play a role in highly specific histone acetylation by tethering transcriptional HATs to specific chromosomal sites<ref> Brownell, J. et al (1996) Curr. Opin. Genet. Dev. 6, 176 [http://www.sciencedirect.com/science/article/pii/S0959437X96800487]<ref/> as well as the assembly of multiprotein complexes in transcriptional activation such as the Bromodomain–HIV-1 Tat complex necessary for HIV-1 transcriptional activation<ref name=f/>.
 == '''Mechanism''' ==