Figure 1: Scheme and low-resolution structure of the mycobacterial ESX-5 translocon. For further details see: Beckham et at. (2017) Nature Microbiology.
Figure 2: Scheme of the peroxisomal translocation cycle (kindly provided by R. Erdmann). Structures of protein components and complexes of the peroxisomal translocation cycle, which have been determined by our group, are indicated by ribbons.
The Wilmanns group aims to unravel the overall architecture of machineries for protein translocation across membranes and mechanisms of molecular elasticity, by employing an integrative structural biology approach complemented by functional experiments.
Current research and future goals
We are investigating the overall structures of challenging protein complexes of biomedical relevance to address major research questions in the infection process of pathogenic bacteria but also in cancer, cardiology and hemostasis. To achieve these goals, we combine X-ray crystallography and single particle cryo-electron microscopy using EMBL-led infrastructures.
Within the center of our research interest is to achieve an in-depth understanding of molecular translocation processes across membranes. A second research focus is to study how proteins react to external forces within the cell by means of molecular elasticity.
Pathogenic mycobacteria comprise distinct type VII secretion machineries that are unrelated to other bacterial secretion systems. These systems are key components for mycobacterial growth and infection. Using a combined structural biology approach, our group has provided first insight into the complete ESX-5 secretion apparatus. Its low-resolution structure reveals a major central pore for transport of folded effector proteins across the inner mycobacterial membrane (Figure 1). We are aiming for high resolution of this structure and to expand our expertise on related secretion systems.
Peroxisomes are cell organelles that allow sequestered metabolic processes central to the viability of living organisms. As peroxisomes have no dedicated protein synthesis machinery, their function depends on the import of protein targets through a peroxisomal membrane translocon. Although the presence of such translocon has been proven, to date any insight into the overall architecture is still missing. While our previous work has mainly focused on the structural elucidation of several translocon sub-complexes involved in substrate recognition and membrane docking (Figure 2), our main future focus will be to unravel the structure of the entire translocon on its own.
Elastic properties of muscle protein complexes
Sarcomeres present the basic unit in cardiac and skeletal muscle cells to provide a molecular framework for their basic function: contraction and relaxation. To cope with the substantial molecular forces generated by this process, sarcomeres are organized by complex networks of in part very long protein filament systems. Our past focus has been on three of those: titin, myomesin and obscurin. By combining knowledge on their structures and single molecule methods to measure their response to external forces, we have found reversible unfolding of exposed helical linkers to present a new novel mechanism of molecular protein elasticity. We are aiming to extend this knowledge into even larger filament complexes and use functional methods to proof these mechanisms to be relevant under physiological conditions.