Research

Living cells and organelles are surrounded by membranes that contain a variety of embedded proteins catalyzing processes that are essential for cells to grow and maintain their activities. My laboratory endeavors to explore the molecular mechanisms of selected membrane proteins including active transporters and oligosaccharyltransferases.
We use X-ray crystallography to determine protein structures at high resolution and in distinct conformations. We also reconstitute the purified proteins in lipid bilayers (proteoliposomes) to investigate their in vitro activities and the conformational changes that underpin their functions.

ABC transporters

ATP-binding cassette (ABC) transporters hydrolyze ATP to drive the translocation of substrates across membranes. ABC importers are expressed in bacteria, where they facilitate the uptake of nutrients. ABC exporters are ubiquitous and catalyze the extrusion of diverse substrates, including drugs, lipids, and peptides. Some ABC exporters contribute to multidrug resistance of cancer cells or bacterial pathogens, whereas the dysfunction of others has been linked to hereditary diseases.
We have determined the first high resolution crystal structures of ABC transporters, revealing distinct protein folds and suggesting basic mechanisms of coupling ATP hydrolysis to substrate translocation. In collaboration, we used electron paramegnetic resonance (EPR) spectroscopy to study intermediate states of the transport reaction that cannot be trapped for crystallographic studies.

MATE transporters

Proteins that catalyze multidrug extrusion belong to several families, including ABC, RND, SMR, MFS, and MATE. We are investigating the mechanisms of multidrug and toxin extrusion (MATE) transporters that couple ion movement to drug export and contribute to antibiotic resistance of pathogenic bacteria, a serious and growing health concern.

Oligosaccharyltransferase

In eukaryotes, more than half of all proteins are glycoproteins, with carbohydrates attached to specific amino acid side chains. The most abundant of these modifications is N-linked glycosylation, where oligosaccharyl ligands are attached to asparagine residues. Several diseases are associated with the dysfunction of this process. In collaboration with the group of Markus Aebi (ETH Zurich), we endeavor to understand the reaction mechanism of N-linked glycosylation at the molecular level.