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NATURE CHEMICAL BIOLOGY
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NATURE PORTFOLIO
DOI: 10.1038/s41589-023-01422-2
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Peptide phage display technique identifies the role of the intervening domain (Int-D) of O-GlcNAc transferase (OGT) in regulating protein-protein interactions and substrate modification. The study reveals the mode of OGT substrate recognition and provides insights into the biological function of the Int-D.
The modification of intracellular proteins with O-linked & beta;-N-acetylglucosamine (O-GlcNAc) moieties is a highly dynamic process that spatiotemporally regulates nearly every important cellular program. Despite its significance, little is known about the substrate recognition and regulation modes of O-GlcNAc transferase (OGT), the primary enzyme responsible for O-GlcNAc addition. In this study, we identified the intervening domain (Int-D), a poorly understood protein fold found only in metazoan OGTs, as a specific regulator of OGT protein-protein interactions and substrate modification. Using proteomic peptide phage display (ProP-PD) coupled with structural, biochemical and cellular characterizations, we discovered a strongly enriched peptide motif, employed by the Int-D to facilitate specific O-GlcNAcylation. We further show that disruption of Int-D binding dysregulates important cellular programs, including response to nutrient deprivation and glucose metabolism. These findings illustrate a mode of OGT substrate recognition and offer key insights into the biological roles of this unique domain. Peptide phage display reveals a non-catalytic binding site on the intervening domain of O-GlcNAc transferase. Its roles in substrate recognition, posttranslational modification (PTM) crosstalk and nutrient response provide insight into the function of this cryptic domain.
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