Aspartate Residues Far from the Active Site Drive O-GlcNAc Transferase Substrate Selection

Journal of the American Chemical Society
Cassandra M JoinerSuzanne Walker

Abstract

O-GlcNAc is an abundant post-translational modification found on nuclear and cytoplasmic proteins in all metazoans. This modification regulates a wide variety of cellular processes, and elevated O-GlcNAc levels have been implicated in cancer progression. A single essential enzyme, O-GlcNAc transferase (OGT), is responsible for all nucleocytoplasmic O-GlcNAcylation. Understanding how this enzyme chooses its substrates is critical for understanding, and potentially manipulating, its functions. Here we use protein microarray technology and proteome-wide glycosylation profiling to show that conserved aspartate residues in the tetratricopeptide repeat (TPR) lumen of OGT drive substrate selection. Changing these residues to alanines alters substrate selectivity and unexpectedly increases rates of protein glycosylation. Our findings support a model where sites of glycosylation for many OGT substrates are determined by TPR domain contacts to substrate side chains five to fifteen residues C-terminal to the glycosite. In addition to guiding design of inhibitors that target OGT's TPR domain, this information will inform efforts to engineer substrates to explore biological functions.

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Citations

Apr 25, 2020·Nucleic Acids Research·Zhi-Wei TanSuzanne Walker
Mar 25, 2020·Chemistry : a European Journal·Arielis EstevezJiaoyang Jiang
Nov 8, 2020·The Journal of Biological Chemistry·Giulia BandiniJohn Samuelson
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Jan 8, 2021·The Journal of Biological Chemistry·Giulia BandiniJohn Samuelson
Jan 22, 2021·Molecular Cancer Research : MCR·Harri M ItkonenIan G Mills
Jun 18, 2021·Frontiers in Chemistry·Xiaoxiao WangLiming Zhao
Aug 3, 2021·Chemical Society Reviews·Abhijit SahaAlberto Fernández-Tejada
Jun 12, 2020·RSC Chemical Biology·Andrii Gorelik, Daan M F van Aalten
Nov 3, 2021·Analytical and Bioanalytical Chemistry·Daniel H RamirezChristina M Woo

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