Structural insights into specific recognition of PTENα/β-NTE by WDR5 in cancer progression

Abstract

AbstractPTENα/β, two variants of PTEN, play a key role in promoting tumor growth by interacting with WDR5 through their N-terminal extensions (NTEs). This interaction facilitates the recruitment of the SET1/MLL methyltransferase complex, resulting in histone H3K4 trimethylation and upregulation of oncogenes such asNOTCH3, which in turn promotes tumor growth. However, the molecular mechanism underlying this interaction has remained elusive. In this study, we determined the crystal structure of PTENα-NTE in complex with WDR5, which reveal that PTENα specifically binds to the WIN site of WDR5 through a novel binding motif specifically found in the NTE domain of PTENα/β. Disruption of this interaction significantly impedes cell proliferation and tumor growth, highlighting the potential of the WIN site inhibitors of WDR5 as therapeutic agents for PTENα/β associated cancers. These findings not only shed light on the important role of the PTENα/β-WDR5 interaction in carcinogenesis, but also present a promising avenue for developing cancer treatments that target this pathway.