Rebekka Wild

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.