O-GlcNAc transferase (OGT) is an essential enzyme that installs O-linked N-acetylglucosamine (O-GlcNAc) to thousands of protein substrates. OGT and its isoforms select from these substrates through the tetratricopeptide repeat (TPR) domain, yet the impact of truncations to the TPR domain on substrate and glycosite selection is unresolved. Here we evaluate the relationship between four major OGT isoforms and the glycoproteins and glycosites that are modified. We find that the first four TPRs of OGT enhance substrate scope, while the last four TPRs of OGT contribute to glycosite selection. This dataset provides a foundation to analyze how perturbations to the TPR domain and expression of OGT isoforms affects the glycosylation of substrates, which will be critical for future efforts in protein engineering of OGT, the biology of OGT isoforms, and diseases associated with the TPR domain of OGT.

Glycoprotein and glycosite selectivity of the TPR domain of OGT

ACS Spring 2022

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