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Life is based on the action and interaction of biomolecules, and measuring their structure and dynamics during their function in the living cell can provide invaluable insights into their mechanism. A prime example for a complex and dynamic protein machinery is clathrin-mediated endocytosis, an essential cellular process for the uptake of molecules from the environment. During endocytosis, more than 50 different proteins in many copies self-assemble into a complex machinery that invaginates the membrane and forms a vesicle. But what are the precise locations of the proteins throughout the process of endocytosis? How can we measure the structural organization and dynamic functional changes of cellular protein assemblies? Current technologies are very limited in answering this question.
Our research vision is to develop optical super-resolution microscopy technologies that will allow us to visualize the structure and the dynamics of molecular machines in living cells on the nanoscale. Our interdisciplinary team of physicists, biologists, computer scientists and engineers are developing new approaches for single-molecule localization microscopy (SMLM) to measure the precise 3D locations of proteins at high throughput and the new MINFLUX technology to probe conformational changes of protein machines in the living cell with nanometer spatial and millisecond temporal resolution. We use these methods to gain mechanistic insights into endocytosis and other cellular protein machines.
Jonas Ries studied physics in Bremen and Konstanz with a specialization in quantum optics. After completing a PhD in biophysics at the TU Dresden in 2008 and a postdoctoral fellowship at the ETH in Zurich in 2012, he joined the EMBL in Heidelberg as a group leader. Since 2023 he is a full professor for Advanced Microscopy and Cellular Dynamics at the Max Perutz labs at the University of Vienna and will start his group in fall 2023.
We developed MINFLUX tracking in 2D and 3D to study the 16 nm steps of the motor protein kinesin while it walks on microtubules in living cells. This is a first step towards monitoring functional conformational changes of protein machines at high spatiotemporal resolution in living systems (Deguchi et al., Science, 2023 - free full PDF version).
We developed high-throughput super-resolution microscopy and measured the nanoscale distribution of 23 endocytic proteins from >100 000 snapshots of endocytic structures in budding yeast, providing new insights into structure, assembly process, and force generation of the endocytic machinery (Mund et al., Cell, 2018).
How can we analyze huge super-resolution data sets in a meaningful way? We developed LocMoFit, a tool that enables fitting of super-resolution microscopy data to an arbitrary geometric model. The fit extracts quantitative parameters of individual cellular structures, which can be used to investigate dynamic and heterogenous protein assemblies and to create average protein distribution maps (Wu et al., Nature Methods, 2023).
We used 3D single-molecule localization microscopy to measure the precise geometry of the clathrin coat at large numbers of endocytic sites. Through pseudo-temporal sorting, we determined the average trajectory of clathrin remodeling during endocytosis. We developed a new physical model that describes the measured shapes and dynamics and could represent a general mechanism for clathrin coat remodeling (Mund, Tschanz et al., Journal of Cell Biology, 2023).
We developed a software that uses simulator-based inference to localize fluorophores in 3D at high densities, increasing the speed of single-molecule localization microscopy by one order of magnitude. This software outperformed all other software in a public software benchmark on all modalities (Speiser, Müller et al., Nature Methods, 2021).