Stein, Alexander, Dr.
Group Leader at the Max Planck Institute for Biophysical Chemistry
- 2008: Dr. rer. nat, Free University of Berlin and MPI for Biophysical Chemistry
- 2008-2009: Postdoctoral Fellow at the MPI for Biophysical Chemistry
- 2010-2014: Postdoctoral Fellow at Harvard Medical School (Boston, USA)
- since 2014: Otto Hahn Group Leader
Major Research Interests
The removal of misfolded proteins is an essential process in all cells. Failure to discard such proteins often results in disease. A particularly intriguing process serves to discard misfolded proteins from the endoplasmic reticulum (ER). The ER does not itself degrade proteins, so a machinery has evolved that moves misfolded proteins into the cytosol where they can be degraded by the proteasome. This retro-translocation process is called ERAD (for ER-associated protein degradation) and is conserved in all eukaryotes. Besides its function in the removal of misfolded proteins, it plays an important role in the controlled degradation of metabolic enzymes, like the ones involved in sterol biosynthesis. The ERAD pathway is also co-opted by certain viruses (e.g. Human cytomegalovirus) and bacterial toxins (e.g. cholera toxin).
Compared to other membrane translocation processes, the mechanism of ERAD is still poorly understood. How are misfolded proteins distinguished from folding intermediates? How are proteins moved across the membrane? How are they extracted from the membrane? How is the energy for membrane translocation provided? The aim of our research is to provide answers to these fundamental questions. To study the mechanism of ERAD we use the budding yeast Saccharomyces cerevisiae as a model organism. We take a bottom-up approach and try to understand the mechanism of ERAD by reconstituting the entire process with purified individual components. These experiments will be complemented by studies in intact yeast cells.
In a second project, we investigate an ERAD-like process that moves proteins into the apicoplast, a plastid-like organell in unicellular parasites, like the malaria parasite Plasmodium falciparum. The apicoplast performs metabolic reactions essential for the parasite's survival, which include the synthesis of lipid precursors, heme and iron-sulfur clusters. The apicoplast is the target of many antimalarial drugs. We hope that a better understanding of its cell biology will facilitate the development of new drugs against malaria.
Homepage Department/Research Group
Selected Recent Publications
- Stein, A., A. Ruggiano, P. Carvalho, and T.A. Rapoport, Key Steps in ERAD of Luminal ER Proteins Reconstituted with Purified Components. Cell, 2014. 158(6): p. 1375-88.
- Hernandez, J.M., A. Stein, E. Behrmann, D. Riedel, A. Cypionka, Z. Farsi, P.J. Walla, S. Raunser, and R. Jahn, Membrane fusion intermediates via directional and full assembly of the SNARE complex. Science, 2012. 336(6088): p. 1581-4
- Stein, A., G. Weber, M.C. Wahl, and R. Jahn, Helical extension of the neuronal SNARE complex into the membrane. Nature, 2009. 460(7254): p. 525-U105.