Dr Lianne Willems
Senior Lecturer
+44 (0)1904 321293
Email: lianne.willems@york.ac.uk
Chemical Biology of Carbohydrates and Carbohydrate-Processing Enzymes
Carbohydrates play key roles in a wide variety of cellular processes. When attached to proteins, they can, for example, regulate protein stability and mediate cell-cell and cell-pathogen interactions. These glycoconjugates are often extended into complex, branched carbohydrate structures. The exact structures of the various glycoconjugates are determined by the enzymes that are responsible for building up, remodelling and breaking down carbohydrate chains. Defects in several of these enzymes, as well as in the glycoconjugates themselves, have been found to be at the basis of various human diseases.
My research is focused on the development of chemical tools to study fundamental processes in glycobiology. By using a multidisciplinary approach, spanning the disciplines of organic chemistry, biochemistry, cell and molecular biology, we can study the cellular roles of carbohydrates and carbohydrate-processing enzymes. With this information, we aim to gain a better understanding of the molecular mechanisms behind their functioning, their impact on cellular physiology and how defects lead to human disease. Current interests include:
- Development of chemical tools to probe and manipulate carbohydrate-processing enzymes and glycans in mammalian cells
- Synthesis of glycoconjugates and carbohydrate analogues
- Characterization of the O-glycosylated proteome
- Structural and mechanistic study of (phospho)glycosyl transferases
Biography
Lianne Willems received her PhD from Leiden University (the Netherlands) in 2014, working with Professor Overkleeft on the topic of activity-based protein profiling. This work comprised the development of novel probes that enable the profiling of the cellular activity of several classes of enzymes, including glycosidases which are key players in the pathology of lysosomal storage disorders.
Narrowing down her research interests in the field of glycobiology, she then went on to postdoctoral research at Simon Fraser University in Canada in the laboratory of Professor Vocadlo. Her research on bioorthogonal chemistry approaches for the functional analysis of O-glycosylation, focusing on processes that occur during protein translation, was awarded with a Banting Postdoctoral Fellowship from the Natural Sciences and Engineering Research Council (NSERC) in Canada as well as a Rubicon fellowship from the Netherlands Organisation of Scientific Research (NWO).
Her current research interests include the development of new chemical tools to study O-glycosylation in relation to human disease, with a major focus on muscular dystrophies. This research is funded by a prestigious ERC starting grant from the European Research Council.
Funding
ERC Starting Grant, Ribitol-phosphate: chemical tools to probe the biology of a unique mammalian carbohydrate (RibiTool), Horizon 2020 (European Research Council), 2020 to 2025.
Selected publications
Huxley, K. E.; Willems, L. I.* Chemical reporters to study mammalian O-glycosylation, Biochem. Soc. Trans. 2021, 49 (2), 903-913.
Verhelst, S. H. L.; Bonger, K. M.; Willems, L. I.* Bioorthogonal Reactions in Activity-Based Protein Profiling, Molecules 2020, 25 (24), 5994.
Zhu Y; Willems LI; Salas D; et al. Tandem Bioorthogonal Labeling Uncovers Endogenous Cotranslationally O-GlcNAc Modified Nascent Proteins. J. Am. Chem. Soc. 2020, 142 (37), 15729–15739.
Tan, H.Y.; Eskandari, R.; Shen, D.; Zhu, Y.; Liu, T.-W.; Willems, L.I.; Alteen, M.G.; Madden, Z.; Vocadlo, D.J. Direct One-Step Fluorescent Labeling of O-GlcNAc-Modified Proteins in Live Cells Using Metabolic Intermediates. J. Am. Chem. Soc. 2018, 140 (45), 15300-15308.
Roth, C.; Chan, S.; Offen, W. A.; Hemsworth, G. R.; Hubbard, R. E.; Willems, L. I.; King, D. T.; Varghese, V.; Britton, R.; Vocadlo, D. J.; Davies, G. J. Structural and functional insight into human O-GlcNAcase. Nat. Chem. Biol. 2017, 13 (6), 610-612.
Willems, L. I.; Murray, B.; Beenakker, T. J.; Scheij, S.; Kallemeijn, W. W.; Boot, R. G.; Verhoek, M.; Donker-Koopman, W. E.; Ferraz, M. J.; van Rijssel, E. R.; Florea, B. I.; Codée, J. D.; van der Marel, G. A.; Aerts, J. M.; Overkleeft, H. S. Potent and selective activity-based probes for GH27 human retaining α-galactosidases, J. Am. Chem. Soc. 2014, 136, 11622-11625.
Willems, L. I.; Li, N.; Florea, B. I.; Ruben, M.; van der Marel, G. A.; Overkleeft, H. S. Triple bioorthogonal ligation strategy for simultaneous labelling of multiple enzymatic activities, Angew. Chem. Int. Ed. 2012, 51, 4431-4434.
Willems, L. I.; van der Linden, W. A.; Li, N.; Li, K.-Y.; Liu, N.; Hoogendoorn, S.; van der Marel, G. A.; Florea, B. I.; Overkleeft, H. S. Bioorthogonal chemistry: applications in activity-based protein profiling, Acc. Chem. Res. 2011, 44, 718-729.
