Cryo-electron microscopy structure of the heparan sulfate polymerase complex with EXT1 colored in orange and EXT2 colored in blue
Rebekka Wild and her research group are investigating the enzymes involved in glycosaminoglycan biosynthesis on an atomic level. Glycosaminoglycans are long and complex sugar chains found on the cell surface of all animal cells, ranging from sea anemone to humans, and they play an important role in diverse biological and pathological processes. The group uses state-of-the art techniques, such as cryo-electron microscopy, to determine 3-dimensional protein structures. They also explore the mechanisms of enzymes by studying chemical reactions in both the test tube and the human cell.
Heparan sulfates are linear, but highly complex polysaccharide chains found on the cell surface of all animal cells. The polysaccharide chain is covalently linked via a serine residue to the core-protein and mediates the interaction with other cellular factors. In doing so, heparan sulfates play a role in a vast number of biological processes, including cell development, lipid metabolism, tissue repair, inflammation, immune responses and host-pathogen interaction. Malfunctioning of heparan sulfate biosynthesis has been linked to Alzheimer’s disease, acute and chronic inflammation, tumorigenesis and diabetes.
Heparan sulfate biosynthesis takes place in the Golgi lumen and involves the fine-tuned interplay of more than a dozen of membrane-anchored glycosyltransferases and glycan-modifying enzymes. Several studies showed that the sequence of heparan sulfate is cell and tissue specific and that it can change during embryonic development, diseases and aging. The regulatory mechanisms, however, remain elusive. In addition, several of the heparan sulfate biosynthesis enzymes were shown to interact with each other and it was proposed that they might assemble into a large super complex, the so-called ‘GAGosome’ and that its composition might define the generated polysaccharide sequence.
We aim to dissect the architecture and catalytic mechanism of the glycosaminoglycan biosynthesis machinery by combining structural biology approaches, in particular single-particle cryo-electron microscopy, with in vitro functional and biophysical assays and in cellulo studies.
• 1st group leader position: 2021, ATIP-Avenir young group leader, Institut de Biologie Structurale in Grenoble, CNRS/CEA/Grenoble Alpes University, France
• 1st permanent position: since 2019: Chargé de recherche (CNRS CRCN, permanent position), Institut de Biologie Structurale in Grenoble, CNRS/CEA/Grenoble Alpes University, France
• Postdoc: 2016-2019: Postdoctoral fellow, ETH Zürich, Switzerland, Kaspar Locher’s lab
• PhD: 2016, Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany and University of Geneva, Switzerland, Michael Hothorn’s lab
• ATIP Avenir grant, 2020
• Prix Schläfli in Biology, Swiss Academy of Sciences, 2019
• Postdoctoral fellowship from the ETH Zürich, 2017
• PhD fellowship from the International Max Planck Research School, Germany, 2016
2017, Protein Science