Moonlighting with WDR5: A Cellular Multitasker

Abstract

WDR5 is a highly conserved WD40 repeat-containing protein that is essential for proper regulation of multiple cellular processes. WDR5 is best characterized as a core scaffolding component of histone methyltransferase complexes, but emerging evidence demonstrates that it does much more, ranging from expanded functions in the nucleus through to controlling the integrity of cell division. The purpose of this review is to describe the current molecular understandings of WDR5, discuss how it participates in diverse cellular processes, and highlight drug discovery efforts around WDR5 that may form the basis of new anti-cancer therapies.

Keywords: WD40 repeat; WDR5; cancer; drug discovery; epigenetics; transcription.

Figure 1

WDR5 is a seven bladed β-propeller protein. (A) This orientation of WDR5 displays the seven β-propeller blades of WDR5 each in a different color. The blades are numbered one to seven from the N-terminus starting with the first full blade. (B) Side view of the orientation of the structure in A. (PDB ID 2H14).

Figure 2

WDR5 is highly conserved in multicellular organisms. Alignment of WDR5 amino acid sequences from indicated species demonstrates high conservation of WDR5 proteins. Colored arrows above sequences indicate the residues involved in each of the seven β-propellers and match the colors in Figure 1. Residues highlighted in red are identical. Residues highlighted in blue are homologous. Homo sapiens (NP_438172.1), Mus musculus (NP_543124.1), Xenopus tropicalis (NP_001011411.1), Drosophila melanogaster (NP_524984.1), Caenorhabditis elegans (Q17963.1), Trichoplax adhaerens (XP_002109498.1).

Figure 3

Two surfaces mediate characterized interactions with WDR5. (A) Surface structure of WDR5 shown from the side. In this orientation, the top face contains the “WDR5-binding motif” (WBM) site, and the bottom face contains the “WDR5-interacting” (Win) site. (B) Top view of the WBM site of WDR5. Residues involved in binding the WBM site are highlighting in orange: Asn225, Tyr228, Leu240, Phe266, Val268, Gln289. (C) Bottom view of WDR5 with residues involved in binding at the Win site highlighted in green: Ala65, Ser91, Asp107, Phe133, Tyr191, Tyr260, Phe263. (PDB 2H14).

Figure 4

The canonical function of WDR5 is as a core component of the SET1/MLL histone methyltransferase complexes. WDR5 functions to scaffold six distinct histone methyltransferase complexes, which catalyze the epigenetic marks of mono-, di-, or tri-methylation at lysine 4 of the peptide tails of histone H3. Two binding sites on WDR5 are required for efficient scaffolding of these complexes. These six complexes differ in the identity of the SET1/MLL protein they carry.

Figure 5

The characterized direct interacting partners of WDR5 have similar motifs. The Win motif and WBM motif sequences for WDR5-interacting proteins mentioned in this review are shown. The Win motifs are all centered on an arginine, while the WBM motifs are a specific combination of acidic and hydrophobic residues. Residues highlighted in red are identical. Residues highlighted in blue are homologous.

Figure 6

WDR5 has various roles at chromatin. (A) WDR5 binds directly to tails of histone H3 that are symmetrically dimethylated on Arg2. WDR5 binding is inhibited by the similar mark of asymmetrical dimethylation on Arg2. (B) WDR5 assembles in the non-specific lethal (NSL) complex, which acetylates histones. (C) WDR5 assembles in an embryonic stem cell-specific form of the nucleosome remodeling and deacetylase (NuRD) complex by binding to the MBD3C subunit. (D) WDR5 directly interacts with the transcription factor MYC to facilitate chromatin binding and transcriptional activation.

Figure 7

WDR5 performs roles at chromatin and roles in cell division. In addition to assembling in multiple complexes at chromatin during interphase, WDR5 functions at the spindle and midbody of dividing cells to facilitate the integrity of mitosis and cytokinesis.