WEHI Wednesday Seminar hosted by Associate Professor Isabelle Lucet
 

Associate Professor Ethan Goddard-Borger
Laboratory Head, ACRF Chemical Biology division – New Medicines & Advanced Technologies Theme, WEHI

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

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

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 tryptophan and 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; developed first-in-class small molecules inhibitors of this enzyme family; 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 intramolecular protein-glycan interactions that drive fold-stabilisation. Collectively, this work sets the stage for the development of new therapeutics for myeloproliferative neoplasms, parasitic diseases and even non-hormonal male contraceptives.

Some recent papers from the Goddard-Borger Lab:

Nature Chemical Biology, 2023, 19, 575-84.

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.

Assoc. Prof. Ethan D. Goddard-Borger obtained his PhD in Chemistry as a Hackett Scholar in 2008 from the University of Western Australia. This work featured the development and commercialisation of a popular diazotransfer reagent that is used extensively across the chemical biology, synthesis and materials science fields. From 2009-2013, Ethan was a CIHR postdoctoral fellow at the University of British Columbia, Canada, with Prof. Stephen G. Withers FRS. During this time he studied the glycobiology of lysosomal storage disorders and developed preclinical drug candidates for some of these diseases. In 2013, Ethan returned to Australia with a VESKI fellowship to establish his independent research program at The Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. His laboratory applies chemical, molecular and structural biology techniques to understanding the roles of protein glycosylation in infectious disease and cancer. Most recently, as a Brian M Davis Centenary Fellow, Ethan and his team have obtained new insights into the abundance, mechanism and role of protein C-glycosylation in health and disease.

All welcome!