WDR5

What is WDR5 protein?

WDR5 gene (WD repeat domain 5) is a protein coding gene which situated on the long arm of chromosome 9 at locus 9q34. This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 7 WD repeats. The WDR5 protein is consisted of 334 amino acids and WDR5 molecular weight is approximately 36.6 kDa.

What is the function of WDR5 protein?

The WDR5 protein is a highly conserved WD40 repeat protein that plays a critical regulatory role in a variety of cellular processes. The most typical function of WDR5 is as the core scaffold component of the histone methyltransferase complex, especially for the methylation of lysine at the fourth position of histone H3, which is closely related to the transcriptional activation of the gene. In addition, WDR5 is involved in processes that control the integrity of cell division. WDR5 is involved in the regulation of gene expression in the nucleus through interactions with a variety of proteins and long non-coding Rnas, including as a component of a variety of histone modification complexes, as well as direct interactions with specific transcription factors.

Fig1. Schematic illustration of WDR5 function in neuroblastoma tumorigenesis. (Qi-lei Han, 2022)

WDR5 related signaling pathway

The WDR5 protein plays multiple roles in signal transduction and is a key regulator of histone methylation modification, particularly during the methylation of histone H3K4. WDR5 promotes transcriptional activation of genes by interacting with the histone methyltransferase complex of the MLL family. In addition, WDR5 also interacts with N-myc protein to form a transcription complex, which plays an important role in the occurrence and development of tumors such as neuroblastoma. WDR5 is also involved in the regulation of cell cycle and DNA replication. The study showed that inhibitors of WDR5 can affect the expression of several genes, including protein synthesis genes, which are closely related to cell growth, proliferation, and survival.

WDR5 related diseases

The WDR5 protein has been implicated in a variety of diseases, and it plays a variety of biological roles within cells. WDR5 is closely associated with the development of neuroblastoma because it is a component of the histone methyltransferase complex. WDR5 is also involved in other types of cancer, including breast and prostate cancer. In addition, dysfunction in WDR5 has been linked to rare diseases such as Noonan syndrome and multiple sclerosis. The latest study also found that WDR5 may be linked to Alzheimer's disease because WDR5 plays an important role in maintaining metabolic and cognitive function in the brain.

Bioapplications of WDR5

The WDR5 protein has an important role in biomedical applications, especially in the field of cancer therapy. The abnormal expression of WDR5 in a variety of tumors is closely related to the occurrence and development of tumors, so it becomes a potential target for cancer therapy. Researchers are developing small molecule inhibitors that target WDR5, which inhibit the proliferation of tumor cells by interfering with the function of WDR5, and are expected to become new anticancer drugs. In addition, inhibitors of WDR5 can also be used in combination with other drugs to produce synergistic effects and enhance anti-tumor effects. These studies provide a new perspective and strategy for the application of WDR5 in the biomedical field.

Case Study 1: Andrew J. Siladi, 2022

WDR5 initiates the formation of complexes that modify histones and plays additional roles in chromatin-related processes. It is a significant target for cancer treatment, with a focus on developing small molecules that target the WIN site, where WDR5 interacts with enzymes responsible for histone H3 lysine 4 methylation (H3K4me). The effectiveness of WIN site inhibitors is believed to stem from their ability to block all WDR5 functions and alter H3K4me, thereby affecting cancer cell transcription. However, this study challenges these assumptions by demonstrating that WIN site inhibition only affects certain WDR5 activities and that changes in H3K4me due to WDR5 degradation do not fully account for the observed transcriptional changes.

Fig1. AIDW cells were treated with 100 μM IAA or 500 nM C16 for the indicated times.

Fig2. Scatter plots comparing log2FC in H3K4me3 versus RNA for IAA-treated AIDW cells.

Case Study 2: Yanran Chen, 2023

The protein WDR5, featuring WD40-repeats, engages with various proteins in and out of the cell nucleus, but the mechanisms controlling its distribution among different complexes are not well understood. This research reveals that EMBOW, a previously undiscovered microprotein encoded by the SCRIB gene, interacts with WDR5, modulating its interactions with partners like KMT2A and KIF2A. EMBOW's expression peaks during late G1 and G2/M phases of the cell cycle. When EMBOW is absent, WDR5's association with KIF2A drops, mitotic spindle length shortens abnormally, the G2/M phase extends, and cell proliferation slows. Conversely, without EMBOW, WDR5's interaction with KMT2A increases, causing WDR5 to bind to non-intended genes, raising H3K4me3 levels and inappropriately activating these genes' transcription.

Fig3. Volcano plot of quantitative proteomics of anti-FLAG pull-down from nuclear lysates of HEK293T cells.

Fig4. WDR5 binding and H3K4me3 levels at three WDR5 target ribosomal genes upon EMBOW KO, shown by ChIP-seq snapshots.

WDR5 has several biochemical functions, for example, . Some of the functions are cooperated with other proteins, some of the functions could acted by WDR5 itself. We selected most functions WDR5 had, and list some proteins which have the same functions with WDR5. You can find most of the proteins on our site.

WDR5 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with WDR5 here. Most of them are supplied by our site. Hope this information will be useful for your research of WDR5.