Goal

We aim to understand the mechanisms of force generation and force perpetuation in AAA+ ATPase motor assemblies.

Members of the large protein superfamily of AAA+ proteins (ATPases associated with various cellular activities) are at the core of many essential multi protein assemblies involved in re-organisation and recycling processes of membranes, proteins or DNA in the cell. They convert chemical energy into mechanical work, and our lab aims to obtain a structural view on the complex conformational dynamics of these fascinating molecular machines in action. In particular, we want to understand how allosteric interactions between AAA+ modules in the active oligomer regulate ATPase activity and how accessory factors influence complex activity.

Hsp104 hexamers in different nucleotide binding states

My recent work on the protein remodeling machine Hsp104 shows that cryo electron microscopy is an essential tool for visualizing assemblies of this complexity, size and dynamic properties in their different physiological states. We now want to address more complex AAA+ assemblies such as the peroxisomal Pex1/Pex6 heterooligomer, adaptor bound Hsp100 oligomers and the 19S proteasomal base complex, which are potential drug targets against severe illnesses such as cancer, Peroxisome Biogenesis Disorders and neurodegenerative disorders. To gain a detailed understanding of the underlying co-operativity and communication in the functional complexes, we seek to integrate structural data obtained by cryo electron microscopy and X-ray crystallography with mutational analysis and biophysical experiments.