Science, Technology and Engineering

Dougan & Truscott Laboratory

Department of Biochemistry

Research - AAA+ proteolytic machines

AAA+ proteases are large molecular machines that use the energy provided by ATP to unfold target proteins and feed them into a degradation chamber. They generally consist of an AAA+ unfoldase (ATPase) associated with a peptidase. The unfoldase can vary in the number of ATPase domains and the nature of its accessory domains imparting specificity to the "gate-keeper" of these machines. The key steps in the protein degradation pathway (as illustrated below) are substrate recognition & delivery, unfolding, translocation and proteolysis. The focus of this area of research is to understand at a molecular level how the motor (unfoldase) works with an emphasis on the contribution of accessory domains. For example how do accessory domains modulate substrate recognition and unfolding? Both bacterial and mitochondrial AAA+ proteases are studied.

Collaborators

Bernd Bukau (ZMBH, Heidelberg, Germany)
Kursad Turgay (Freie University Berlin, Germany)

Recent publications

• Kirstein J, Molière N, Dougan DA, Turgay K. (2009)
  Adapting the machine: adaptor proteins for Hsp100/Clp and AAA+ proteases.
  Nature Reviews Microbiology 7, 589-599
• Kirstein J, Schlothauer T, DOUGAN DA, Lilie H, Tischendorf G, Mogk A, Bukau B, Turgay K. (2006)
  Adaptor protein controlled oligomerization activates the AAA+ protein ClpC. EMBO J., 5, 1481-91.
• Weibezahn J, Tessarz P, Schlieker C, Zahn R, Maglica Z, Lee S, Zentgraf H, Weber-Ban EU, DOUGAN DA, Tsai FT, Mogk A, Bukau B. (2004) Thermotolerance Requires Refolding of Aggregated Proteins by Substrate Translocation through the Central Pore of ClpB. Cell. 119, 653-65.