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spinqualitylabelsall models Apo BRPF1 Bromodomain solved via solution NMR. (PDB entry 2d9e) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Overview 2 PZP Domain 3 Bromodomain Structure & Acetyllysine Recognition 4 PWWP Domain 5 Role in Disease Progression Overview Peregrin, also known as Bromodomain and PHD Finger-containing 1 (BRPF1) is a 137 kDa protein that plays a versatile role in epigenetic signaling events. It contains three chromatin reader domains, including a , (two PDH fingers separated by a Zinc Knuckle), and proline-tryptophan-tryptophan-proline () domain [1]. Through these three domains, it is capable of recognizing both modified and unmodified histones, as well as non-specifically binding DNA [2],[3]. BRPF1 carries out its function as a component of the MOZ (monocytic leukemic zinc-finger protein) histone acetyltransferase (HAT) complex [4]. This complex is involved in the regulation of gene expression, particularly those involved with skeletal development and hematopoiesis [5],[6]. PZP Domain Bromodomain Structure & Acetyllysine Recognition Consistent with most bromodomains, the BRPF1 bromodomain consists of a four α-helical bundle. These helices are termed (from N to C terminus)[7]. The BRPF1 bromodomain has been shown to recognize and bind to various acetylated lysine marks on the N-terminal tails of histones tails [3]. 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) [4],[8]. Interestingly, the BRPF1 bromodomain has also been shown to bind di-acetylated histone peptides with high affinity, including H4K5acK8ac and H4K5acK12ac [4]. 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 involved in coordinating histone H4 ligands (I27, L34, E36, V37, N83, and I88)[4]. Notably, asparagine 83 was among these. The interactions 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 [4],[7]. PWWP Domain Role in Disease Progression BRPF1 has been implicated in the progression of several cancers. Chromosomal translocations of the gene encoding BRPF1 have been linked to the development of acute myeloid leukemia [4]. Another study reported an association between upregulation of the BRPF1 gene and poor survival rates in hepatocellular carcinoma patients [9]. Mutations within the gene itself have been associated with neurological disorders and widespread reduced histone acetylation [1].

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. ↑ 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} 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} 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. ↑ 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
9. ↑ 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