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Tandem Bioorthogonal Labeling Uncovers Endogenous Cotranslationally O-GlcNAc Modified Nascent Proteins

By September 14, 2020September 21st, 2020No Comments

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This week we profile a recent publication in the Journal of the American Chemical Society
from Dr. Yanping Zhu (pictured below) in the laboratory of Dr. David Vocadlo (pictured above) at SFU.

Dr. Vocadlo, can you provide a brief overview of your lab’s current research focus?

I head the Laboratory for Chemical Glycobiology at Simon Fraser University, and we are focused on developing chemical and biochemical tools to evaluate the roles of glycans in physiological processes using various disease models. Glycans are chains of different types of sugar units that are attached to each other and onto proteins and lipids. They coat all cells from every kingdom of life and are emerging as important mediators of a range of physiological processes. Various agencies around the world, including the NIH in the USA and the Network of Centres of Excellence (NCE), known as GlycoNet here in Canada, have launched initiatives to understand glycosylation and exploit this knowledge for the benefit of humans.

Yanping Zhu

Yanping Zhu

What is the significance of the findings in this publication?

In this work, Drs. Zhu and Willems, now a faculty member at the University of York in the UK, along with their colleagues, were studying a form of glycosylation found on proteins inside the cytoplasm. Levels of this sugar modification, known as O-GlcNAc, change depending on nutrient availability. We have long speculated that O-GlcNAc is involved in proteostasis of a subset of proteins. We built on research showing the enzyme that installs O-GlcNAc associates with ribosomes and our initial observation that O-GlcNAc can occur co-translationally. In this paper, the team went on to use sophisticated chemical biology approaches in combination with proteomic analyses to identify the first set of co-translationally O-GlcNAc modified proteins. The findings reported here suggest that O-GlcNAc glycosylation may act to regulate cellular proteostasis in a manner akin to the well described process of N-glycosylation within the secretory pathway.

What are the next steps for this research?

With about 75 proteins now being identified as co-translationally modified, the stage is set to understand the physiological functions of this process. For example, does the extent of co-translational modification vary in response to nutrient availability and does this contribute to regulating the levels of these modified proteins? Further, what is the fate of co-translationally installed O-GlcNAc?

This work was funded by:

We are really grateful for funding from NSERC for support of chemical biology tool development and for support of this research from the CIHR. Dr. Daniela Salas and Prof. Leonard Foster at UBC were our excellent collaborators and carried out the MS-based proteomic studies – Genome Canada and Genome BC provide essential support of this essential MS infrastructure.

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