Nearly every process in a living cell is carried out by protein complexes with highly organized structure. These “molecular machines” use cellular sources of energy to drive structural rearrangements that serve specific function, such as assembly or disassembly of macromolecular complexes, macromolecular transport etc. Among highly sophisticated protein machines, the AAA+ superfamily of proteins has recently attracted attention of researchers. AAA stands for “ATPases associated with a variety of cellular activities”, which implies that these proteins use energy from ATP and perform a variety of functions, they share, however, specific amino-acid sequence motifs and common structural and biochemical properties.

Our research is currently focused on two sub-families within the AAA+ superfamily: bacterial Clp ATPases and human torsins. Our previous studies have shown that ClpB cooperates with other bacterial molecular chaperones in efficient disaggregation and reactivation of misfolded and aggregated proteins. It has been shown that the ClpB/DnaK/DnaJ/GrpE system assists hundreds of cellular proteins in bacteria under stress, such as heat shock. The mechanism of ClpB-assisted protein reactivation is, however, currently unknown.

Electron-microscopy images of ClpB with an ATP analog (left) and without nucleotides in a low-salt buffer (right). Formation of oligomeric rings is a common structural feature of AAA+ ATPases.

Torsins are a novel family of AAA+ proteins recently identified in humans and other higher eukaryotes. A single mutation in a member of this family, torsinA, has been shown to correlate with dystonia, a neurological disease associated with movement disorders in humans. Initial studies suggest that torsinA may be a novel chaperone located in the secretory pathway. However, specific function of torsinA and the link between torsinA and dystonia are unknown.

Self-portrait by Egon Schiele (Austria, 1890-1918) shows characteristic symptoms of dystonia.

Our laboratory performs basic research oriented towards understanding molecular mechanisms underlying the function of AAA+ proteins. In our research, we use a combination of biological, biochemical and biophysical experimental approaches to study interactions between proteins, protein localization inside living cells, and structural changes in proteins and protein complexes.