Research Area: Cell Death and Biophysics, molecular and cellular Biology, Biochemistry and advanced Microscopy
Apoptotic cell death is essential for diverse processes such as development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is a central event in the execution of apoptosis and plays a key role in its inflammatory outcome. Knowledge of the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis. Our recent work revealed that Bax and Bak dimers form distinct line, arc and ring-like assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and the mechanisms controlling the spatiotemporal formation and range of action of apoptotic foci are currently not known.
Molecular mechanisms of Bcl-2 proteins:
Bcl-2 family members are essential regulators of apoptosis that control permeabilization of the mitochondrial outer membrane, leading to release of apoptotic factors into the cytosol, activation of caspases and cell death. The Bcl-2 family has antiapoptotic and proapoptotic members as well as protein sensors for apoptotic stimuli and initiation of apoptosis. The reasons why Bcl-2 family members have opposing functions despite their high degree of homology remain obscure, and the basis for interaction between different members of the family to decide whether or not apoptosis is induced remains poorly understood. Translocation of Bcl-2 members to the mitochondrial membrane is of high interest, since the effect of the membrane environment on their function is unknown. Our research focuses on the role of the membrane and specific lipids, and on the interaction network between the Bcl-2 members that decides whether or not apoptosis is induced.
Model membranes and optical microscopy:
To investigate dynamic processes in biological membranes we apply model systems of different complexity, ranging from pure lipid bilayers to cultured cells. A common feature of these systems is that they can be visualized with optical microscopy and can be used for experiments involving time-lapse microscopy, FRAP, FRET, FCS, AFM and other advanced microscopy techniques. In recent years, we have focused on implementing new methods to quantify the stoichiometry and molecular architecture of macromolecular complexes based on single molecule imaging and super resolution microscopy.
We offer a multi-disciplinary project that combines multiple approaches aimed at determining the molecular architecture and dynamics of assembly of apoptotic foci. These include:
Our work focuses on the study of membrane processes from a quantitative point of view. To address our questions in the fields of protein-membrane interactions, in pore formation and in membrane dynamics during regulated cell death, we use quantitative methods based on advanced fluorescence microscopy applied to a combination of synthetically reconstituted systems and living cells.
We pioneered the use of single molecule techniques to investigate the mechanism of pore formation by the apoptotic executors Bax and Bak and the interaction of the Bcl-2 proteins.
We are looking for a highly motivated and enthusiastic person with a Masters’ degree in biophysics, cell biology or biochemistry. Experience in cell death signaling, mitochondrial biology or advanced light microscopy techniques would be a bonus, but is not a prerequisite.