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Consistent with other bromodomains, the BRPF1 bromodomain consists of a four α-helical bundle. These helices are termed <scene name='91/910741/Helical_bundle/3'>αZ, αA, αB, and αC</scene> (from N to C terminus)<ref name="Lubula_2014">PMID:25281266</ref>. There are <scene name='91/910741/Za_bc_loop/1'>two loop motifs</scene> present in its structure. The ZA loop links together the αZ and αA helices, while the BC loop links αB and αC<ref name="Lubula_2014" />.
Consistent with other bromodomains, the BRPF1 bromodomain consists of a four α-helical bundle. These helices are termed <scene name='91/910741/Helical_bundle/3'>αZ, αA, αB, and αC</scene> (from N to C terminus)<ref name="Lubula_2014">PMID:25281266</ref>. There are <scene name='91/910741/Za_bc_loop/1'>two loop motifs</scene> present in its structure. The ZA loop links together the αZ and αA helices, while the BC loop links αB and αC<ref name="Lubula_2014" />.
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[[Image:Kac N83 PyMOL Image.JPG | thumb | 400x400px | BRPF1 Asn-83 forms a hydrogen bond with the carbonyl of the acetyllysine moiety. (PDB entry 4QYD)]]
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[[Image:Kac N83 PyMOL Image.JPG | thumb | 400x400px | BRPF1 Asn-83 forms a hydrogen bond with the carbonyl moiety of the acetyllysine residue. (PDB entry 4QYD)]]
The BRPF1 bromodomain has been shown to recognize and bind to various acetylated lysine marks on the N-terminal tails of histones tails <ref name="Glass1" />. Using isothermal titration calorimetry (ITC) experiments, it was found that the BRPF1 bromodomain preferentially binds to histone H4 acetylated at positions K5 ([[2rs9]]) and K12 ([[4qyd]]) as well as H2A at position K5 ([[4qyl]]) <ref name="Obi" />,<ref name="Glass1" />. Interestingly, the BRPF1 bromodomain has also been shown to bind di-acetylated histone peptides with high affinity, including H4K5acK8ac and H4K5acK12ac <ref name="Obi" />. Acetyllysine recognition is coordinated by a number of residues in the bromodomain's binding pocket. Using NMR chemical shift perturbation experiments, Glass et al. reported several <scene name='91/910741/Nmr_resi_h4_binding/1'>key residues</scene> the undergo conformational changes upon histone H4 ligand binding (I27, L34, E36, V37, N83, and I88)<ref name="Obi" />. Notably, asparagine 83 was among these. The interaction between the amide nitrogen of asparagine with the carbonyl of the acetyllysine group is conserved in all bromodomains and is necessary for binding to occur <ref name ="Obi" />,<ref name ="Lubula_2014" />.
The BRPF1 bromodomain has been shown to recognize and bind to various acetylated lysine marks on the N-terminal tails of histones tails <ref name="Glass1" />. Using isothermal titration calorimetry (ITC) experiments, it was found that the BRPF1 bromodomain preferentially binds to histone H4 acetylated at positions K5 ([[2rs9]]) and K12 ([[4qyd]]) as well as H2A at position K5 ([[4qyl]]) <ref name="Obi" />,<ref name="Glass1" />. Interestingly, the BRPF1 bromodomain has also been shown to bind di-acetylated histone peptides with high affinity, including H4K5acK8ac and H4K5acK12ac <ref name="Obi" />. Acetyllysine recognition is coordinated by a number of residues in the bromodomain's binding pocket. Using NMR chemical shift perturbation experiments, Glass et al. reported several <scene name='91/910741/Nmr_resi_h4_binding/1'>key residues</scene> the undergo conformational changes upon histone H4 ligand binding (I27, L34, E36, V37, N83, and I88)<ref name="Obi" />. Notably, asparagine 83 was among these. The interaction between the amide nitrogen of asparagine with the carbonyl of the acetyllysine group is conserved in all bromodomains and is necessary for binding to occur <ref name ="Obi" />,<ref name ="Lubula_2014" />.

Revision as of 05:06, 3 May 2022

Apo BRPF1 Bromodomain solved via solution NMR. (PDB entry 2d9e)

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  1. ↑ 1.0 1.1 Yan K, Rousseau J, Littlejohn RO, Kiss C, Lehman A, Rosenfeld JA, Stumpel CT, Stegmann AP, Robak L, Scaglia F, Nguyen TT, Fu H, Ajeawung NF, Camurri MV, Li L, Gardham A, Panis B, Almannai M, Sacoto MJ, Baskin B, Ruivenkamp C, Xia F, Bi W, Cho MT, Potjer TP, Santen GW, Parker MJ, Canham N, McKinnon M, Potocki L, MacKenzie JJ, Roeder ER, Campeau PM, Yang XJ. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation. Am J Hum Genet. 2017 Jan 5;100(1):91-104. doi: 10.1016/j.ajhg.2016.11.011. Epub, 2016 Dec 8. PMID:27939640 doi:http://dx.doi.org/10.1016/j.ajhg.2016.11.011
  2. ↑ 2.0 2.1 2.2 2.3 Klein BJ, Cox KL, Jang SM, Cote J, Poirier MG, Kutateladze TG. Molecular Basis for the PZP Domain of BRPF1 Association with Chromatin. Structure. 2019 Nov 6. pii: S0969-2126(19)30355-7. doi:, 10.1016/j.str.2019.10.014. PMID:31711755 doi:http://dx.doi.org/10.1016/j.str.2019.10.014
  3. ↑ 3.0 3.1 3.2 Poplawski A, Hu K, Lee W, Natesan S, Peng D, Carlson S, Shi X, Balaz S, Markley JL, Glass KC. Molecular insights into the recognition of N-terminal histone modifications by the BRPF1 bromodomain. J Mol Biol. 2014 Apr 17;426(8):1661-76. doi: 10.1016/j.jmb.2013.12.007. Epub 2013, Dec 12. PMID:24333487 doi:http://dx.doi.org/10.1016/j.jmb.2013.12.007
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Obi JO, Lubula MY, Cornilescu G, Henrickson A, McGuire K, Evans CM, Phillips M, Boyson SP, Demeler B, Markley JL, Glass KC. The BRPF1 bromodomain is a molecular reader of di-acetyllysine. Curr Res Struct Biol. 2020;2:104-115. doi: 10.1016/j.crstbi.2020.05.001. Epub, 2020 May 12. PMID:33554132 doi:http://dx.doi.org/10.1016/j.crstbi.2020.05.001
  5. ↑ Hibiya K, Katsumoto T, Kondo T, Kitabayashi I, Kudo A. Brpf1, a subunit of the MOZ histone acetyl transferase complex, maintains expression of anterior and posterior Hox genes for proper patterning of craniofacial and caudal skeletons. Dev Biol. 2009 May 15;329(2):176-90. doi: 10.1016/j.ydbio.2009.02.021. Epub 2009 , Feb 27. PMID:19254709 doi:http://dx.doi.org/10.1016/j.ydbio.2009.02.021
  6. ↑ You L, Li L, Zou J, Yan K, Belle J, Nijnik A, Wang E, Yang XJ. BRPF1 is essential for development of fetal hematopoietic stem cells. J Clin Invest. 2016 Sep 1;126(9):3247-62. doi: 10.1172/JCI80711. Epub 2016 Aug 8. PMID:27500495 doi:http://dx.doi.org/10.1172/JCI80711
  7. ↑ 7.0 7.1 7.2 Lubula MY, Eckenroth BE, Carlson S, Poplawski A, Chruszcz M, Glass KC. Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain. FEBS Lett. 2014 Sep 30. pii: S0014-5793(14)00705-4. doi:, 10.1016/j.febslet.2014.09.028. PMID:25281266 doi:http://dx.doi.org/10.1016/j.febslet.2014.09.028
  8. ↑ Lalonde ME, Avvakumov N, Glass KC, Joncas FH, Saksouk N, Holliday M, Paquet E, Yan K, Tong Q, Klein BJ, Tan S, Yang XJ, Kutateladze TG, Cote J. Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity. Genes Dev. 2013 Sep 15;27(18):2009-24. doi: 10.1101/gad.223396.113. PMID:24065767 doi:http://dx.doi.org/10.1101/gad.223396.113
  9. ↑ 9.0 9.1 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
  10. ↑ Cheng CL, Tsang FH, Wei L, Chen M, Chin DW, Shen J, Law CT, Lee D, Wong CC, Ng IO, Wong CM. Bromodomain-containing protein BRPF1 is a therapeutic target for liver cancer. Commun Biol. 2021 Jul 20;4(1):888. doi: 10.1038/s42003-021-02405-6. PMID:34285329 doi:http://dx.doi.org/10.1038/s42003-021-02405-6

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