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Deciphering the prevalence, mechanism and function of protein C-glycosylation

Abstract

Tryptophan C-mannosylation is the only form of protein glycosylation featuring a C–C bond between protein and glycan. It occurs in metazoans and apicomplexan parasites, where it plays a key role in stabilising a subset of secreted proteins. The distribution and abundance of this protein modification throughout the proteome is not well understood. Likewise, little is known about how this unusual C–C bond between L-tryptophan and D-mannose is formed, or how this type of glycosylation is able to stabilise protein folds. My laboratory has taken a multipronged approach to addressing these unknowns. We have developed enrichment methods to facilitate the proteomic mapping of the C-glycome in complex tissues; applied a combination of chemical and structural biology techniques to understand the enzymatic mechanism of C–C bond formation; and pioneered the synthetic methodology required to prepare an exhaustive array of chemically-homogenous glycoproteins. We have used the latter to quantitate the impact of C-glycosylation on the thermal stability and thermodynamics of protein folding that, when coupled with molecular dynamics simulations, provide rigorous insights into the protein-glycan interactions driving fold-stabilisation. Collectively, this work sets the stage for the development of tools to enable the post-translational control of protein expression.

Some recent papers from the Goddard-Borger Lab

Nature Chemical Biology, 2023, https://doi.org/10.1038/s41589-022-01219-9.

Nature Communications, 2022, 13 (1), 4400.

PNAS, 2022, 119 (4), e2116022119.

Nature Chemical Biology, 2021, 17 (4), 428-437.

Journal of the American Chemical Society, 2021, 143 (32), 12699-12707.

Nature Communications, 2020, 11 (1), 2265.

Nature Communications, 2017, 8 (1), 561.

Nature Chemical Biology, 2016, 12 (4), 215-7.