There is no research on the relationship between BRPF3 PWWP domain and any human disease. However, both of its closely related domains BRPF1 and BRPF2 PWWP domains are associated with hox gene regulation, that is associated with schizophrenia and bipolar affective disorder.<ref>Bjarkam CR, Corydon TJ, Olsen IM, Pallesen J, Nyegaard M, Fryland T, Mors O, Børglum AD. Further immunohistochemical characterization of BRD1 a new susceptibility gene for schizophrenia and bipolar affective disorder. Brain Structure and Function. 2009 Dec 1;214(1):37.</ref> Therefore BRPF3 PWWP domain, which has very similar β-barrel structure with previous proteins, may also have Hox gene-related function. But a further research would be required.
There is no research on the relationship between BRPF3 PWWP domain and any human disease. However, both of its closely related domains BRPF1 and BRPF2 PWWP domains are associated with hox gene regulation, that is associated with schizophrenia and bipolar affective disorder.<ref>Bjarkam CR, Corydon TJ, Olsen IM, Pallesen J, Nyegaard M, Fryland T, Mors O, Børglum AD. Further immunohistochemical characterization of BRD1 a new susceptibility gene for schizophrenia and bipolar affective disorder. Brain Structure and Function. 2009 Dec 1;214(1):37.</ref><ref>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 1;135(11):1935-46.</ref> Therefore BRPF3 PWWP domain, which has very similar β-barrel structure with previous proteins, may also have Hox gene-related function. But a further research would be required.
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
Revision as of 18:35, 28 April 2020
This Sandbox is Reserved from Jan 13 through July 31, 2020 for use in the course Protein Structure in Drug Discovery taught by Karen C. Glass at the ACPHS, Colchester, United States. This reservation includes Sandbox Reserved 895 through Sandbox Reserved 901.
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The PWWP domain belongs to the Royal family, which consists of Tudor, chromodomain, MBT(Malignant Brain Tumor), and PWWP domains. The PWWP domain was first identified as a structural motif includes 100 to 130 amino acids in WHSC1 protein research. The researchers named after its very conservative sequence, Pro-Trp-Trp-Pro located at the β2 strand of protein.[1] This domain is mainly related to the recognition of methylated histone tail lysine and related to the epigenetic regulation of genes. BRPF1 PWWP domain, which has very similar structure with 3pfs, presents on actively transcribing cells and may regulate Hox A9 gene which is related to MOZ-TIF2-dependant leukemia.[2] The 3pfs motif is relatively mystery we may assume that 3pfs also do similar works
Structure
The main characteristic of PWWP domains is the two distinctive substructural motifs: β-barrel at the N-terminal region and helixes at C-terminal region.[3] The β-barrel is a very conservative feature of PWWP domains and the one at 3pfs is composed of 5 β-strands. The helixes at the C-terminal region are very different and 3pfs has 3 helixes which are little more than many of its relatives. The Pro-Trp-Trp-Pro motif, which is the most conservative, is little different in 3pfs, just like its closely-related proteins. The PWWP domains in BRPF family are composed of Tyr-Pro-Ser-Tyr and may suggest they would have a similar affinity. The stability of domain comes from both inter-substructure and intra-substructure interactions including hydrogen bonds and polar interactions. One unique feature of PWWP motif is that the first position affects the stability and aggregation of the protein. The proline gives more stability and oligomerization to the protein, compared to the alanine at the same position.[4]
Figure 1: Cartoon model of 3PFS motif. β-sheets(magenta) and helixes(orange) are shown. generated in PyMOL using PDB: 3PFS
Function
Methyl-lysine reader
PWWP domains are one of epigenetic regulators which recognize specific lysine residues which are methylated. Even though there is no detailed research on 3pfs, it may be assumed to have similar function with BRPF1 PWWP domain which is shown to have methylated histone binding activity.[5] With a high-throughput mass spectrometry screening, this motif is suggested as an essential motif of histone 3 lysine 36 trimethylation binding.[6] The β-strands and Pro-Trp-Trp-Pro motif form hydrophobic cavity, which is the binding site of methylated lysines.[7] Since the aromatic cage is a common structure in the Royal family, it can be a common tool for methylated lysine binding.[8]
Nonspecific binding
The PWWP domains have a significant amount of basic residues which gives ability of nonspecific binding on DNA strands.[9] BRPF3 3pfs protein has 11 lysine residues and 12 arginine residues. These residues' sidechains remain being positively charged on in vivo pH. The DNA strand phosphate backbone, which is negatively charged, would be attracted to PWWP domain surface due to the nature of attraction between the opposite charges.
Figure 2: Lysine(yellow) and Arginine(red) residues on 3PFS surface interacting with DNA backbone generated in PyMOL using PDB: 3PFS
Evolutionary conservations
PWWP domain is only found in eukaryotes, from a yeast to a human. The number of PWWP containing protein is also varying on species; the human has 20. The loyal family has a common structural characteristic, three conserved β-strands.[10] The PWWP domain is also believed to be evolved from a common ancestor which had 3 β-strands. The most conservative section is the PWWP sequence, which it is named after.
Therapheutic features
There is no research on the relationship between BRPF3 PWWP domain and any human disease. However, both of its closely related domains BRPF1 and BRPF2 PWWP domains are associated with hox gene regulation, that is associated with schizophrenia and bipolar affective disorder.[11][12] Therefore BRPF3 PWWP domain, which has very similar β-barrel structure with previous proteins, may also have Hox gene-related function. But a further research would be required.
This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
↑Rona GB, Eleutherio EC, Pinheiro AS. PWWP domains and their modes of sensing DNA and histone methylated lysines. Biophysical reviews. 2016 Mar 1;8(1):63-74.
↑Vezzoli A, Bonadies N, Allen MD, Freund SM, Santiveri CM, Kvinlaug BT, Huntly BJ, Göttgens B, Bycroft M. Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1. Nature structural & molecular biology. 2010 May;17(5):617-9.
↑Rona GB, Eleutherio EC, Pinheiro AS. PWWP domains and their modes of sensing DNA and histone methylated lysines. Biophysical reviews. 2016 Mar 1;8(1):63-74.
↑Hung YL, Lee HJ, Jiang I, Lin SC, Lo WC, Lin YJ, Sue SC. The first residue of the PWWP motif modulates HATH domain binding, Stability, and Protein–Protein Interaction. Biochemistry. 2015 Jul 7;54(26):4063-74.
↑Vezzoli A, Bonadies N, Allen MD, Freund SM, Santiveri CM, Kvinlaug BT, Huntly BJ, Göttgens B, Bycroft M. Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1. Nature structural & molecular biology. 2010 May;17(5):617-9.
↑Vermeulen M, Eberl HC, Matarese F, Marks H, Denissov S, Butter F, Lee KK, Olsen JV, Hyman AA, Stunnenberg HG, Mann M. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell. 2010 Sep 17;142(6):967-80.
↑Rona GB, Eleutherio EC, Pinheiro AS. PWWP domains and their modes of sensing DNA and histone methylated lysines. Biophysical reviews. 2016 Mar 1;8(1):63-74.
↑Qiu Y, Zhang W, Zhao C, Wang Y, Wang W, Zhang J, Zhang Z, Li G, Shi Y, Tu X, Wu J. Solution structure of the Pdp1 PWWP domain reveals its unique binding sites for methylated H4K20 and DNA. Biochemical Journal. 2012 Mar 15;442(3):527-38.
↑Qiu C, Sawada K, Zhang X, Cheng X. The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds. Nature structural biology. 2002 Mar;9(3):217-24.
↑Rona GB, Eleutherio EC, Pinheiro AS. PWWP domains and their modes of sensing DNA and histone methylated lysines. Biophysical reviews. 2016 Mar 1;8(1):63-74.
↑Bjarkam CR, Corydon TJ, Olsen IM, Pallesen J, Nyegaard M, Fryland T, Mors O, Børglum AD. Further immunohistochemical characterization of BRD1 a new susceptibility gene for schizophrenia and bipolar affective disorder. Brain Structure and Function. 2009 Dec 1;214(1):37.
↑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 1;135(11):1935-46.
