Structure, Function and Inhibition of ClpP Proteases
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Beschreibung
ClpP proteases are conserved enzymes that play important roles in protein quality control, protein homeostasis and virulence regulation in pathogenic bacteria. In concert with chaperones from the AAA+ family of ATPases such as ClpX, ClpP degrades a variety of substrates including damaged or misfolded proteins as well as regulatory proteins. A tetradecameric serine protease, ClpP is composed by two heptameric rings that form a barrel-like structure with fourteen active sites inside of the degradation chamber. In the ClpXP complex, hexameric ClpX binds on top of ClpP, thereby generating a central pore through which substrates are threaded. While ClpX is responsible for substrate engagement and unfolding, ClpP acts as the proteolytic core for fast and processive protein degradation. This dissertation covers three main aspects of ClpP proteases:
(i) Structural analysis of ClpP from pathogenic Staphylococcus aureus uncovered a regulator switch preventing uncontrolled proteolysis through a coupling of oligomerization to activity.
(ii) The determination of cleavage site specificities provided insights into enzyme function as well as enhanced substrates for activity measurements. Disease-associated mutants of the human ClpP enzyme were studied and ClpP heterooligomerization was shown to act as activation mechanism.
(iii) Three different modes of inhibition are described, ranging from blockage of the active site, to disruption of oligomerization and dehydroalanine formation of the catalytic serine.
About the author:
Malte Gersch obtained a B.Sc. degree in Chemistry and Biochemistry from Ludwig Maximilians University Munich (LMU). After a visiting research fellowship at Stanford University and a M.Sc. with honors from LMU, he joined the lab of Prof. Dr. Stephan Sieber at the Technische Universität München (TUM) for his PhD. This dissertation focuses on ClpP proteases with regards to their structure, function and inhibition. The author gratefully acknowledges fellowships from the German National Academic Foundation and from the Chemical Industry Funds (FCI).
Autor*in
Malte Gersch