WD40 repeat domain proteins: a novel target class?

Abstract

Antagonism of protein-protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. However, successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets as opposed to the much more common large, flat protein interaction surfaces. Here we review one of the most abundant PPI domains in the human proteome, the WD40 repeat domain (WDR), which has a central peptide-binding pocket. Recently, two WDR proteins, WDR5 and EED, have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDRs represent a novel target class for drug discovery? While clinical validation remains to be seen, a cautious optimism is justified, considering the ubiquitous involvement of WDR proteins across multiple disease-associated pathways. The druggability and structural diversity of WDR binding pockets suggest that this prevalent domain class could open-up areas of biology that have so far resisted drug discovery efforts.

Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer

“…In recent years, targeting PPIs as indicators for clinical diagnosis and therapeutic interventions has become a promising but challenging approach in the field . The focus on WDR domain proteins has increased because of its function as a broad mediator of PPIs . We proposed that hubs (strong connections with other proteins) among WDR domain proteins may be more essential than other non‐hubs to the pathology of CRC.…”

“…We proposed that hubs (strong connections with other proteins) among WDR domain proteins may be more essential than other non‐hubs to the pathology of CRC. In our study, we first constructed a bioinformatics strategy, which combined a network hub analysis and CRC‐associated gene analysis based on publicly available data, to identify candidates potentially involved in CRC from 361 known WDR domain proteins . Indeed, genome‐wide studies have shown that deletion of a hub protein is more likely to be lethal than deletion of a non‐hub protein, a phenomenon known as the centrality‐lethality rule .…”

“…As knowledge of PPIs increases, more opportunities for targeting diseases are likely to be found from the human protein interactome . One of the most abundant protein interaction domains in humans is the WD40 repeat (WDR) domain, such that more than 360 domains are currently annotated . The WDR domain typically exhibits a seven‐bladed β‐propeller architecture with an overall doughnut shape, with which WDR domain‐containing proteins mediate PPIs or protein‐DNA interactions .…”

“…WDR domain proteins are involved in a wide spectrum of cellular networks, and as a consequence, perturbations in many of these proteins have been associated with human diseases, including CRC. Inactivating mutations of FBXW7 are frequently detected in CRC, and these mutations interrupt the interactions between FBXW7 and its substrates by disrupting the structural integrity of the WDR domain.…”

“…In our study, we searched for candidates involved in CRC from among 361 known WDR domain proteins by bioinformatics analysis and selected one (WDR54) for further investigation. The expression of WDR54 was demonstrated to be elevated in CRC, and its high expression in tumors was shown to predict a poor prognosis in CRC patients.…”