What are ATPases associated with diverse cellular activities (AAA+)?

AAA+ enzymes (ATPases associated with various cellular activities) are a heterogenous group of molecular motor proteins. They usually generate mechanical work from binding and decomposing ATP (adenosine triphosphate), the universal energy source in the cell. AAA+ proteins usually act as oligomers and are often found at the core of essential multi protein assemblies involved in re-organisation and recycling processes of proteins, membranes or DNA in the cell. Despite sharing a strongly conserved nucleotide binding domain (see Figure), each AAA+ protein exhibits unique functional specificity and substrate selectivity. It is believed that accessory domains and proteins facilitate fine tuning of the AAA+ motor activity and thus confer specificity. However, the nature of these interactions as well as their impact on the motor activity of the AAA+ domains remains to be established.

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. The ultimate goal is to integrate structural data obtained by cryo electron microscopy and X-ray crystallography with mutational analysis and biophysical experiments in order to tackle severe disorders and illnesses stemming from malfunctioning molecular machines. 

Publication:

Wendler, P., S. Ciniawsky, M. Kock, S. Kube (2012). Structure and function of the AAA+ nucleotide binding pocket. Biochim Biophys Acta  1823(1):2-4.

http://www.sciencedirect.com/science/article/pii/S0167488911001790

 

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Left: All AAA+ proteins share a highly conserved ATP binding domain of approx. 230 residues. They belong to the superfamily of P-loop ATPases and contain several conserved motifs including Walker A (light blue), Walker B (dark blue), Arginine Finger (green), Glutamate Switch (orange), Sensor 1 (pink) and Sensor 2 (red). Right: The active form of most AAA+ proteins is a hexamer.