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Overview

Bromodomain and PHD finger-containing protein family is the group of proteins found in higher eukaryotes. The members have similar structural features and believed to be an essential part of interaction on H3K36me3.^[1] The PWWP motif, a part of BRPF proteins, 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.^[2] This domain is mainly related to the recognition of specific methylated histone tail lysine and epigenetic regulation of genes. Unlike BRPF1 and 2, BRPF3 is less studied by the researchers. Therefore many of its function remains unknown.

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] 3PFS has a β-barrel composed of 5 β-strands, which is a very conservative feature of PWWP domains. The helixes at the C-terminal region are not very conservative; 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 a little different from its name, just like its closely-related proteins. The PWWP domains in the 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 the PWWP motif is that the first position of arrangement 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 1A: Cartoon model of 3PFS motif. β-sheets(magenta) and helixes(orange) are shown. generated in PyMOL using PDB: 3PFS

Figure 1B: The alignment of BRPF1 PWWP domain and BRPF3 PWWP domain. The green box indicates the 'PWWP' motif. generated in Tcoffee using PDB: 3PFS', '2X35

Function

Methyl-lysine reader

PWWP domains are one of the epigenetic regulators which recognize specific lysine residues that 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, 3PFS is also suggested as an essential domain of histone 3 lysine 36 trimethylation binding.^[6] The aromatic residues on 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]

Figure 2: Surface of 3PFS with PWWP motif(green) is indicated. generated in PyMOL using PDB: 3PFS

Nonspecific binding

The PWWP domains have a significant amount of basic residues which gives the 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 the PWWP domain surface due to the nature of attraction between the opposite charges.

Figure 3: 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 varies on species; a man has 20 PWWP containing proteins. The loyal family has a common structural characteristic, three conserved β-strands.^[10] Therefore, PWWP domains are believed to be evolved from a common ancestor which had 3 β-strands. Using the domain-tree approach, the BRPF family has branched out from rest of PWWP domain-containing proteins early and evolved itself.^[11] As a domain, the PWWP presents in both unicellular and multicellular organisms. However, proteins of unicellular organisms are not found in multicellular creatures. Therefore, the PWWP domain was transmitted as a conserved linear arrangement alone, not with the whole protein.^[12]

Therapheutic features

There is no research on the relationship between the 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. BRPF1 PWWP domain presents on actively transcribing cells and may regulate Hox A9 gene which is related to MOZ-TIF2-dependant leukemia.^[13] BRPF2 is also related to Hox gene which is associated with schizophrenia and bipolar affective disorder.^[14] The BRPF3 PWWP domain may also have Hox gene-related function since it has a very similar structure with its family members. However, further research would be required for more understandings.

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