Biogenesis and functioning of membrane proteins

Inner membrane proteins play an important role in the functioning of the bacterial cell envelope, including energy metabolism, cell division and signal transduction. For cell division a large multi-subunit complex, also known as divisome, is formed at the center of the cell. The assembly of this complex follows a strict hierarchy and is tightly regulated. The main function of the divisome is contraction of the membrane and septum formation. In our section, we are studying the role of FtsQ in divisome formation and cell division. FtsQ is a minor inner membrane protein with a large periplasmic domain. Because FtsQ performs an essential function, but is present in small quantities, the hypothesis is that this protein could be an interesting target for the development of antibacterial compounds. 

A second project concerns the biogenesis of tail-anchored (TA) membrane proteins. These proteins carry their targeting signal at the extreme C-terminus of the protein suggestive of an unusual post-translational targeting mechanism. Whilst it is increasingly clear that TA proteins can be integrated into a variety of biological membranes, the vast majority of studies to date have focused on the Endoplasmic Reticulum. The result is that our current knowledge and understanding of the components and pathways responsible for TA protein biogenesis at other locations is minimal. In this project we study TA protein biogenesis at the E. coli and mycobacterial inner membrane. In addition to providing fundamental mechanistic insights, these studies will also create a platform that will enable us to pursue drug-based therapies for tuberculosis that specifically target mycobacterial TA protein biogenesis. Furthermore, these biological membrane targets are particularly well suited to our goal of performing a detailed investigation of the influence of bilayer phospholipid composition upon TA protein integration within a physiologically relevant context.

A third project concerns the Bam complex that playsa pivotal role in biogenesis of the outer membrane that surrounds Gram-negative bacteria. It forms the key machinery responsible for the insertion and assembly of outer membrane proteins. The Bam complex is also required for type V protein secretion (see previous research theme) and thus relevant to bacterial virulence in a wide range of pathogens. In contrast to almost all other outer membrane proteins, two subunits of the Bam complex are essential for bacterial growth, while other subunits play important roles in membrane permeability and virulence. In addition, its strategic position in the outer membrane makes the Bam complex highly accessible towards inhibitory compounds and insensitive to the action of drug efflux pumps. Together, these properties characterize the Bam machinery as a novel prime target for antibiotic intervention. We therefore aim to identify inhibitors of the Bam complex that could serve as novel antibiotics. For this, we develop high throughput cell-based functional assays. In complementary, more fundamental studies we investigate the structure and function of the Bam complex, in particular in the context of type V secretion.