RSS

PDB:2H13

Protein Name

Histon modification protein WRD5 / histon subunit H3 complex

Species

Human

Biological Context

Most genomic DNAs of eukaryotes are tightly packaged as chromatin in the cell nucleus. The base unit of chromatin is termed nucleosome. It is a histone octamer wound by DNA of 146 base pairs with 1.75 super-helical turns (Fig.1). Multiple nucleosomes are connected like beads and form a fiber. A chromatin is formed by rolling and condensing the fiber. A histone octamer consists of two copies each of the core histone proteins H2A, H2B, H3, and H4. Peptide of 20 - 30 residues near N-terminus of H3 and H4 is called histone-tail, and it is chemically modified by methylation, phosphorylation, acetylation, etc.

With this modification pattern (termed histon code), chromatin expresses various functions. For example, it is noted that methylation of H3-K4 (4th lysine of H3) work to activate gene transcription, and methylation of H3-K9 (9th lysine of H3) work to inhibit gene transcription. Moreover, it is noted that phosphorylation of H3-S10 (10th serine of H3) is related to cell division. By controlling the histone code freely, one may be able to activate or inactivate the expression of target genes. Thus, proteins involved in histone code are well studied. WDR5 (WD40 repeat structure) protein is one of them. WDR5 is a subunit of TRX (histone methyltransferase complexes). It selectively binds to K4me2 (4th dimethylated lysine) of the histone H3. The WDR5 bound with H3 recruits TRX, and promotes the trimethylation of K4me2 by TRX.

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(Fig.1) Nucleosome

Structure Description

2h132h13_x2h13_y

The crystal structure of WDR5 (residues 22-334) bound to a 10-residue histone H3 peptide bearing K4me2 was determined. The overall structure of WDR5 consists of seven WD40 repeats called β-propeller blades. Each of WD40 comprises four-stranded anti-parallel β-sheet like blade of propeller. Although they closely resembles to each other, the sixth WD40 is slightly distorted compared to the other WD40. H3 peptide takes 3-10 helix structure. The N-terminus of H3 peptide is settled into the cavity formed in the center of seven WD40, and is anchored to WDR5 by a series of hydrogen bonds and van der Waals contacts in this portion (Fig.3) (Fig.4). Unexpectedly, K4me2 is exposed to the solvent and is not in direct interactions with WDR5. On the other hand, R2 and T3 form many interactions with WDR5. It has been experimentally demonstrated that WDR5 does not bind to H3 when three N-terminal residues (A1, R2, T3) of H3 peptide are substituted with other residues. Furthermore, it was reported that WDR5 binds to H3 without discriminating among different degrees of K4 methylation. Thus, 3 residues, A1, R2, and T3 , but not K4me2, are the most important in H3 recognition by WRD3. Large conformational changes in the WDR5 are not induced upon histone H3 binding. To mention slight change, the aromatic side chains of Phe133 and Phe263 rotate to form the phenylalanine clamp that sandwiches the R2 guanidinium group. In addition, Ile305 and Leu321 shift slightly toward H3 peptide in order to make van der Waals contacts with R2 and T3, respectively.

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(Fig.2) WDR5 complexed with H3 peptide
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(Fig.3) Binding site (Fig.4) Interactions network of binding site

Protein Data Bank (PDB)

References

Source

  • Couture, J.F. Collazo, E. Trievel, R.C.; "Molecular recognition of histone H3 by the WD40 protein WDR5."; Nat.Struct.Mol.Biol.; (2006) 13:698-703 PubMed:16829960.

Others

author: Jun-ichi Ito


Japanese version:PDB:2H13