Regulation of AAA+ proteolytic machines

AAA+ (ATPases associated with a variety of cellular activities) proteases are a ubiquitous group of proteins that are found in all kingdoms of life, from bacteria to mammals. They form large molecular machines that use the energy provided from hydrolysis of ATP, to unfold target proteins and feed them into a degradation chamber. Generally, they consist of an AAA+ unfoldase (ATPase) component (e.g. ClpX) in association with a peptidase component (e.g. ClpP).

The key steps in the protein degradation pathway are (1) substrate recognition and delivery, (2) unfolding and translocation, and (3) proteolysis. The unfoldase component is largely responsible for substrate recognition, however the specificity of these machines may often be extended (or altered) by specific AAA+ co-factors known as adaptor proteins.

A major focus of our research involves the molecular dissection of these machines, how they work, the substrates they recognise and the proteins that influence their substrate-binding repertoire. Currently we are studying a number of different AAA+ proteins, from a variety of bacterial species (both pathogenic and non-pathogenic) and, in collaboration with Dr Kaye Truscott, from mammalian mitochondria.