Sandbox Reserved 654: Difference between revisions
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<Structure load='1JM4' size='500' frame='true' align='right' caption='This is a model of the pheylalanine hydroxylase dimer as found in humans. The green ball in within each subunit represents the iron ion in the catalytic domains.' scene='Insert optional scene name here' /> | <Structure load='1JM4' size='500' frame='true' align='right' caption='This is a model of the pheylalanine hydroxylase dimer as found in humans. The green ball in within each subunit represents the iron ion in the catalytic domains.' scene='Insert optional scene name here' /> | ||
The bromodomain is an evolutionary conserved motif found in chromatin remodeling complexes. It has been | The bromodomain is an evolutionary conserved motif found in chromatin remodeling complexes. It has been identified in over 100 proteins from multiple organisms ranging from unicellular microscopic eukaryotes (e.g., yeast) to humans. The motif is best known for the groundbreaking recent discoveries made to identify it as the only acetyl-lysine binding domain, Dhalluin, C. et al (1999) Nature 399, 491, and to reveal its highly specific ligand selectivity properties. Zeng, L. (2002) FEBS 513:1, 124. Due to these novel characteristics, bromodomains are typically found in proteins responsible for modifications in chromatin structure and the regulation of gene expression, such as histone acetyltransferases (HATs), and the ATPase subunits of chromatin remodeling complexes. There are several families of proteins with bromodomains. One such family is the human transcriptional coactivator p300/CBP-associated factor (PCAF) bromodomain, <ref> sample ref </ref> | ||
== '''Structure and Function''' == | == '''Structure and Function''' == | ||
== Structure == | |||
The bromodomain was originally identified as a sequence of roughly 60 amino acid residues that forms 2 alpha helices. Haynes, S.R. et al (1992) Nucleic Acids Res. 20, 2603. However, it is now known that the bromodomain consist of a highly conserved sequence of approximately 110 amino acids. Owen, D. J. et al. (2000) EMBO J. 19(22), 6141. The structure of the PCAF bromodomain consists of a four-helix bundle (alphaZ, aA,aB, and aC) with a left-handed twist, and a long intervening loop between helices Z and A (ZA loop). Dhalluin. The ZA loop of the bromodomain has a defined conformation and is packed against the loop between helices aB and aC (BC loop) to form a hydrophobic pocket. This pocket created by the ZA and BC loops is lined by specific residues (Val 752, Ala 757, Tyr 760, Val 763, Tyr 802 and Tyr 809) that support protein-protein interactions. The ZA loop varies in length between different bromodomains, but almost always contains residues corresponding to Phe 748, Pro 751, Pro 758, Tyr 760 and Pro 767. Dhalluin. | The bromodomain was originally identified as a sequence of roughly 60 amino acid residues that forms 2 alpha helices. Haynes, S.R. et al (1992) Nucleic Acids Res. 20, 2603. However, it is now known that the bromodomain consist of a highly conserved sequence of approximately 110 amino acids. Owen, D. J. et al. (2000) EMBO J. 19(22), 6141. The structure of the PCAF bromodomain consists of a four-helix bundle (alphaZ, aA,aB, and aC) with a left-handed twist, and a long intervening loop between helices Z and A (ZA loop). Dhalluin. The ZA loop of the bromodomain has a defined conformation and is packed against the loop between helices aB and aC (BC loop) to form a hydrophobic pocket. This pocket created by the ZA and BC loops is lined by specific residues (Val 752, Ala 757, Tyr 760, Val 763, Tyr 802 and Tyr 809) that support protein-protein interactions. The ZA loop varies in length between different bromodomains, but almost always contains residues corresponding to Phe 748, Pro 751, Pro 758, Tyr 760 and Pro 767. Dhalluin. | ||
== Function == | |||
The hydrophobic pocket formed by the loops is the primary binding site for acetyl-lysine proteins. 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. Mujtaba, S. et al (2007) Oncogene 26, 5521. 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. Mujtaba, S. et al (2002) Mol. Cell 9, 575. | The hydrophobic pocket formed by the loops is the primary binding site for acetyl-lysine proteins. 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. Mujtaba, S. et al (2007) Oncogene 26, 5521. 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. Mujtaba, S. et al (2002) Mol. Cell 9, 575. | ||
