User:Mulu Lubula/Sandbox 1

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=BRPF1 Bromodomain=
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===BRPF1 Bromodomain===
==General description==
==General description==

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Contents

BRPF1 Bromodomain

General description

PDB ID 2d9e

Drag the structure with the mouse to rotate
Like all known bromodomains, the BRPF1 bromodamain adopts a conserved structural fold of a left-handed bundle of four helices (αZ, αA, αB, and αC ) with the inter-helical ZA and BC loops having variable length and sequence[1][2]. This variable regions make a hydrophobic pocket constituting the binding site. 2d9e
Gene: BRPF1 (Homo sapiens)
Resources: FirstGlance, OCA, RCSB, PDBsum, TOPSAN
Coordinates: save as pdb, mmCIF, xml


Schematic representation of the MOZ/MORF histone acetyltransferase (HAT) complex with different subunits shown in different colors. The Brpf1 subunit contains a unique combination of domains including two PHD fingers, a bromodomain and a PWWP domain.An sequence alignment of the BRPF1 bromodomain with other bromodomains in the family 5 of bromodomains was created with Expresso (using stuctural information), and is shown in the lower portion of the image. Location of structural elements are at the top of the alignment above the BRPF1 bromodomain, which is used as a reference for amino acid numbering.
Schematic representation of the MOZ/MORF histone acetyltransferase (HAT) complex with different subunits shown in different colors. The Brpf1 subunit contains a unique combination of domains including two PHD fingers, a bromodomain and a PWWP domain[3].An sequence alignment of the BRPF1 bromodomain with other bromodomains in the family 5 of bromodomains was created with Expresso (using stuctural information), and is shown in the lower portion of the image. Location of structural elements are at the top of the alignment above the BRPF1 bromodomain, which is used as a reference for amino acid numbering.

Covalent modifications of histone tails play a key role in determining the outcome of many nuclear processes including transcription, DNA repair, recombination, and replication[4]. It is central to cell homeostasis, as alterations in chromatin structure contribute to the development of cancer[5] and other human diseases (For a video describing the importance of histone modifications on gene expression click here). In human, translocation of the MOZ/MORF histone acetyltransferase (HAT) complex has been linked to a subtype of acute myeloid leukemia (AML)[6]. MOZ/MORF forms tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1, -2, or -3[7]. BRPF proteins have been shown to bridge the association of MOZ/MORF with ING5 and EAF6. Deletion mapping studies have also revealed that the acetyltransferase domain of MOZ/MORF is sufficient for BRPF1 interaction[8]. BRPF proteins therefore play a key role in assembling and activating MOZ/MORF acetyltransferase complexes. Brpf1 contains a unique combination of domains typically found in chromatin-associated factors, including PHD fingers, a bromodomain and a PWWP domain[9]. These domains help recruit MOZ/MORF to distinct sites of active chromatin. Bromodomains are highly conserved motifs generally known to bind (read) histones acetylated at their lysine residues. Despite their highly conserved αZ, αA, αB, and αC regions, variations in the αAZ and αBC regions of bromodomains help them distinguish between different acetylated lysine residues[10]. Although it may be expected that, like all known bromodomains, the BRPF1 bromodomain can recognize/read acetylated lysine, the exact modification(s) that this bromodomain can recognize are still subject to elucidation.


Structural description

Like all known bromodomains, the BRPF1 bromodamain adopts a conserved structural fold of a left-handed bundle of four helices (αZ, αA, αB, and αC ) with the inter-helical ZA and BC loops having variable length and sequence[11]. The latter loops constitute a hydrophobic pocket serving to stabilize the structure as well as to interact with the acetyl-lysine.

Cartoon showing the solution structure of the bromodomain of human BRPF1 in complex with histone H4K5ac peptide (PDB2RS9). Like all known bromodomains, the BRPF1 bromodamain adopts a conserved structural fold of a left-handed bundle of four helices (αZ, αA, αB, and αC ) with the inter-helical ZA and BC loops having variable length and sequence. This variable regions make a hydrophobic pocket constituting the binding site. The BRPF1 Bromodomain is shown in green, and the H4K5ac ligand is in blue. This Cartoon was generated by using PyMol
Cartoon showing the solution structure of the bromodomain of human BRPF1 in complex with histone H4K5ac peptide (PDB2RS9). Like all known bromodomains, the BRPF1 bromodamain adopts a conserved structural fold of a left-handed bundle of four helices (αZ, αA, αB, and αC ) with the inter-helical ZA and BC loops having variable length and sequence[12]. This variable regions make a hydrophobic pocket constituting the binding site. The BRPF1 Bromodomain is shown in green, and the H4K5ac ligand is in blue. This Cartoon was generated by using PyMol



Structural insigts into function

Based on the observed high sequence similarity with well characterized bromodomains, the BRPF1 bromodomain may be expected to recognize/read acetylated lysine(AML)[13]. However additional studies are needed to identify the exact modifications that the BRPF1 bromodomain may recognize/read.

References

  1. ↑ Laue K, Daujat S, Crump JG, Plaster N, Roehl HH, Kimmel CB, Schneider R, Hammerschmidt M. The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development. 2008 Jun;135(11):1935-46. doi: 10.1242/dev.017160. PMID:18469222 doi:10.1242/dev.017160
  2. ↑ Avvakumov N, Cote J. The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene. 2007 Aug 13;26(37):5395-407. PMID:17694081 doi:10.1038/sj.onc.1210608
  3. ↑ Laue K, Daujat S, Crump JG, Plaster N, Roehl HH, Kimmel CB, Schneider R, Hammerschmidt M. The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development. 2008 Jun;135(11):1935-46. doi: 10.1242/dev.017160. PMID:18469222 doi:10.1242/dev.017160
  4. ↑ Avvakumov N, Cote J. The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene. 2007 Aug 13;26(37):5395-407. PMID:17694081 doi:10.1038/sj.onc.1210608
  5. ↑ Avvakumov N, Cote J. The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene. 2007 Aug 13;26(37):5395-407. PMID:17694081 doi:10.1038/sj.onc.1210608
  6. ↑ Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C, Tahmasebi S, Cayrou C, Doyon Y, Goh SL, Champagne N, Cote J, Yang XJ. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol Cell Biol. 2008 Nov;28(22):6828-43. doi: 10.1128/MCB.01297-08. Epub 2008 Sep , 15. PMID:18794358 doi:10.1128/MCB.01297-08
  7. ↑ McCullagh P, Chaplin T, Meerabux J, Grenzelias D, Lillington D, Poulsom R, Gregorini A, Saha V, Young BD. The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene. Oncogene. 1999 Dec 9;18(52):7442-52. PMID:10602503 doi:10.1038/sj.onc.1203117
  8. ↑ Doyon Y, Cayrou C, Ullah M, Landry AJ, Cote V, Selleck W, Lane WS, Tan S, Yang XJ, Cote J. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell. 2006 Jan 6;21(1):51-64. PMID:16387653 doi:10.1016/j.molcel.2005.12.007
  9. ↑ Laue K, Daujat S, Crump JG, Plaster N, Roehl HH, Kimmel CB, Schneider R, Hammerschmidt M. The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development. 2008 Jun;135(11):1935-46. doi: 10.1242/dev.017160. PMID:18469222 doi:10.1242/dev.017160
  10. ↑ Guo F, Lin PR, Li YQ, Su XL, Wang DD, Zhou TH. [BRPF2, a novel transcript of BRPF1 and their expression in mice tissues]. Yi Chuan. 2013 Jan;35(1):79-84. PMID:23357268
  11. ↑ Laue K, Daujat S, Crump JG, Plaster N, Roehl HH, Kimmel CB, Schneider R, Hammerschmidt M. The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development. 2008 Jun;135(11):1935-46. doi: 10.1242/dev.017160. PMID:18469222 doi:10.1242/dev.017160
  12. ↑ Laue K, Daujat S, Crump JG, Plaster N, Roehl HH, Kimmel CB, Schneider R, Hammerschmidt M. The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development. 2008 Jun;135(11):1935-46. doi: 10.1242/dev.017160. PMID:18469222 doi:10.1242/dev.017160
  13. ↑ Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C, Tahmasebi S, Cayrou C, Doyon Y, Goh SL, Champagne N, Cote J, Yang XJ. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol Cell Biol. 2008 Nov;28(22):6828-43. doi: 10.1128/MCB.01297-08. Epub 2008 Sep , 15. PMID:18794358 doi:10.1128/MCB.01297-08

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