RSS

PDB:2F6J

Protein Name

BPTF PHD finger-linker-bromodomain bound to H3K4me3

Species

Homo sapiens (human)

Biological Context

Although DNA (or its components, the nucleotides, A, T, G and C) is a key element of genetic information, another mechanism called epigenetics also plays an important role in genetic regulations. Epigenetics is a mechanism for selective activation or inactivation of genes, thus regulating gene expression. More concretely, epigenetic regulating factors includes, for instance, DNA methylation, histone modification and chromatin structure.

One of the important histone modifications for epigenetic regulation is the methylation of lysine residues in the histone protein. In particular, it is reported that histone H3 trimethylated at lysine4 (H3K4me3) is associated with transcription start sites of active genes. However, because methylation is a common modification among histone proteins, it has been unclear how H3K4me3 is specifically recognized.

The structure shown here reveals that a PHD finger motif of human BPTF subunit, which is the largest subunit of the ATP-dependent chromatin-remodelling complex NURF, binds to H3K4me3 specifically but not to other methylated lysines. Previously, the PHD finger had been an uncharacterized chromatin-binding domain found in a large number of chromatin-associated proteins. As it works for recognition of methylation modification, further investigation for a wide variety of chromatin-associated proteins and modification-binding modules is expected.

Structure Description

2f6j2f6j_x2f6j_y

Figures 1 and 2 show the crystal structure of human BPTF PHD finger-linker-bromodomain bound to H3 (1-15) K4me3. An anti-parallel β-sheet was formed between the PHD finger (K21-D27) and the N terminus (A1-T6) of H3. Besides, the long side-chains of both R2 and K4me3 of H3 clip an invariant tryptophan (W32) of the PHD finger. The spacing of R2-T3-K4me3 enables the recognition of W32 from both sides. The residues (Y10, Y17, Y23 and W32) surrounding K4me3 are hydrophobic and thus the trimethylated form makes the most appropriate environment for the binding of the PHD finger compared with the di- mono- and non-methylated ones (Fig. 3). Furthermore the N terminal end of H3 is anchored to the PHD finger by a pair of hydrogen bonds.

For these reasons, PHD finger can specifically bind K4me3, discriminating a number of other lysine residues.

2F6J_cartoon (Fig. 1) BPTF PHD finger-linker-bromodomain bound to H3K4me3

The complex of BPTF PHD finger(blue)-linker(red)-bromodomain(green) and H3(1-15)K4me3 peptide (space-filling representation).
2F6J_structure (Fig. 2) H3K4me3 on the surface of the PHD finger domain

Positioning of the H3K4me3 peptide (space-filling representation) on the surface of the PHD finger-linker-bromodomain (surface representation).
2F6J_sticks (Fig. 3) Side-chains surrounding the K4me3

Positioning of the H3K4me3 peptide (A1-T6 backbone segment with side-chains of R2 and K4me3, green) with a four-aromatic-amino-acid cage of the BPTF PHD finger (side chains of Y10, Y17, Y23 and W32, blue) for the trimethylated lysine (K4me3).

Protein Data Bank (PDB)

References

Source

Li, H. Ilin, S. Wang, W. Duncan, E.M. Wysocka, J. Allis, C.D. Patel, D.J.; "Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF."; Nature; (2006) 442:91-95 PubMed:16728978.

Others

author: Naoya Fujita


Japanese version:PDB:2F6J