User:Brian Boyle/Sandbox 1: Difference between revisions

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

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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 bromodomain, PZP domain (two PHD fingers separated by a Zinc Knuckle), and proline-tryptophan-tryptophan-proline (PWWP) domain (from N to C terminus)^[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

The PZP domain of BRPF1 has been shown to associate with the histone H3 tail, as well as DNA^[2]. Three residues in the H3 peptide undergo unique interactions with the binding pocket. These are Ala-1, Arg-2, and Thr-3.^[2].

Bromodomain Structure & Acetyllysine Recognition

Consistent with other bromodomains, the BRPF1 bromodomain consists of a four α-helical bundle. These helices are termed αZ, αA, αB, and αC (from N to C terminus)^[7]. There are two loop motifs present in its structure. The ZA loop links together the αZ and αA helices, while the BC loop links αB and αC^[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]. It preferentially binds to histone H4 acetylated at positions K5 (2rs9), K8, and K12 (4qyd) as well as H3 and H2A ((4qyl) at position K14 and K5, respectively^[4],^[3]. 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 key residues the undergo conformational changes upon histone H4 ligand binding (I27, L34, E36, V37, N83, and I88)^[4]. 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 ^[4],^[7]. Furthermore, the tyrosine 40 and isoleucine 127 stabilize the acetyllysine residue through water-mediated hydrogen bonds^[7].

PWWP Domain

↑ 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:https://dx.doi.org/10.1016/j.ajhg.2016.11.011
↑ ^2.0 ^2.1 ^2.2 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:https://dx.doi.org/10.1016/j.str.2019.10.014
↑ ^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:https://dx.doi.org/10.1016/j.jmb.2013.12.007
↑ ^4.0 ^4.1 ^4.2 ^4.3 ^4.4 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:https://dx.doi.org/10.1016/j.crstbi.2020.05.001
↑ 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:https://dx.doi.org/10.1016/j.ydbio.2009.02.021
↑ 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:https://dx.doi.org/10.1172/JCI80711
↑ ^7.0 ^7.1 ^7.2 ^7.3 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:https://dx.doi.org/10.1016/j.febslet.2014.09.028

BRPF1 Association with the MOZ HAT Complex

The MOZ Histone Acetyltransferase Complex is a tetramer consisting of MEAF6, ING5, BRPF1 and MOZ or MORF^[1]. Within BRPF1, there are two non-chromatin-binding modules surrounding the PZP domain that are responsible for its association with the MOZ HAT Complex. On the N-terminal side of the PZP, lies the MOZ/MORF binding domain^[2]. On the other side of the PZP domain, there is a small module involved in binding to ING5 and MEAF6^[3]. BRPF1 seems to be required for the formation of the MOZ HAT complex, as it acts as a bridge associating MOZ or MORF with ING5 and MEAF6^[3].

Evolutionary Relationships

Bromodomains are categorized into several families based on sequence and structural similarity. The BRPF1 bromodomain belongs to family IV of bromodomains^[4].

Links to Human Disease

BRPF1 has been implicated in the progression of several cancers. Chromosomal translocations of the gene encoding MOZ (a subunit in the MOZ HAT complex) have been linked to the development of acute myeloid leukemia ^[5]. The crucial role of BRPF1 in this complex has made it the subject of many studies in order to understand how this mutation leads to a cancer phenotype. Another study reported an association between upregulation of the BRPF1 gene and poor survival rates in hepatocellular carcinoma patients ^[6].

Mutations within the gene itself have been associated with neurological disorders and widespread reduced histone acetylation ^[7].

Available Structures

References

↑ Cite error: Invalid <ref> tag; no text was provided for refs named Klein
↑ 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:https://dx.doi.org/10.1101/gad.223396.113
↑ ^3.0 ^3.1 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
↑ Lloyd JT, Glass KC. Biological function and histone recognition of family IV bromodomain-containing proteins. J Cell Physiol. 2018 Mar;233(3):1877-1886. doi: 10.1002/jcp.26010. Epub 2017 Jun , 13. PMID:28500727 doi:https://dx.doi.org/10.1002/jcp.26010
↑ Cite error: Invalid <ref> tag; no text was provided for refs named Obi
↑ 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:https://dx.doi.org/10.1038/s42003-021-02405-6
↑ Cite error: Invalid <ref> tag; no text was provided for refs named Yan

Proteopedia Page Contributors and Editors (what is this?)

Brian Boyle

[Yan-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:https://dx.doi.org/10.1016/j.ajhg.2016.11.011

[Klein-2] 2.0 ^2.1 ^2.2 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:https://dx.doi.org/10.1016/j.str.2019.10.014

[Glass1-3] 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:https://dx.doi.org/10.1016/j.jmb.2013.12.007

[Obi-4] 4.0 ^4.1 ^4.2 ^4.3 ^4.4 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:https://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:https://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:https://dx.doi.org/10.1172/JCI80711

[Lubula_2014-7] 7.0 ^7.1 ^7.2 ^7.3 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:https://dx.doi.org/10.1016/j.febslet.2014.09.028

[Klein-1] Cite error: Invalid <ref> tag; no text was provided for refs named Klein

[Lalonde-2] 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:https://dx.doi.org/10.1101/gad.223396.113

[Ullah-3] 3.0 ^3.1 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

[Lloyd-4] Lloyd JT, Glass KC. Biological function and histone recognition of family IV bromodomain-containing proteins. J Cell Physiol. 2018 Mar;233(3):1877-1886. doi: 10.1002/jcp.26010. Epub 2017 Jun , 13. PMID:28500727 doi:https://dx.doi.org/10.1002/jcp.26010

[Obi-5] Cite error: Invalid <ref> tag; no text was provided for refs named Obi

[6] 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:https://dx.doi.org/10.1038/s42003-021-02405-6

[Yan-7] Cite error: Invalid <ref> tag; no text was provided for refs named Yan

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@@ Line 13: / Line 13: @@
 [[Image:Kac N83 PyMOL Image.JPG | thumb | 400x400px | BRPF1 Asn-83 forms a hydrogen bond with the carbonyl moiety of the acetyllysine residue. The bromodomain is shown in green. The H4K12ac peptide is shown in cyan. (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" />. It preferentially binds to histone H4 acetylated at positions K5 ([[2rs9]]), K8, and K12 ([[4qyd]]) as well as H3 and H2A (([[4qyl]]) at position K14 and K5, respectively<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" />. Furthermore, the tyrosine 40 and isoleucine 127 stabilize the acetyllysine residue through water-mediated hydrogen bonds<ref name="Lubula_2014" />.
 == '''PWWP Domain''' ==

User:Brian Boyle/Sandbox 1: Difference between revisions

Revision as of 19:45, 3 May 2022

Contents

Overview

PZP Domain

Bromodomain Structure & Acetyllysine Recognition

PWWP Domain

Contents

BRPF1 Association with the MOZ HAT Complex

Evolutionary Relationships

Links to Human Disease

Available Structures

References

Proteopedia Page Contributors and Editors (what is this?)

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