Nagpal, J., Truscott, K.N. & Dougan, D.A.
La Trobe Institute for Molecular Science, Department of Biochemistry, La Trobe University, Melbourne, 3086 AUSTRALIA
Regulated proteolysis plays a crucial role in maintaining protein homeostasis in the cell, from the removal of unwanted or misfolded proteins, to the control of the cellular stress response pathways. In bacteria, these processes are controlled by a number of different proteases, including the highly conserved serine protease ClpP. In most bacterial species, ClpP is expressed as a zymogen which following autocatalytic removal of its propeptide, forms a large oligomeric complex composed of 14 identical subunits. Interestingly, Mycobacterium tuberculosis (Mtb) – the causative agent of Tuberculosis (TB) and Mycobacterium smegmatis (Msm) – a close non-pathogenic relative of Mtb, encode two ClpP homologs (ClpP1 and ClpP2), only one of which contains a putative propeptide. Recently however, both ClpP homologs were shown to be essential for Mtb growth during infection and it was proposed that both proteins form an active hetero-oligomeric complex (ClpP1/ClpP2), which in turn is proposed to function together with one or both ATP-dependent unfoldases (ClpX and/or ClpC). However, the composition of these ATP-dependent proteolytic complexes and the molecular details of ClpP1/ClpP2 complex formation currently remains poorly understood. Based on a series of biochemical experiments, using wild type and mutant forms of MsmClpP1 and MsmClpP2 we propose a model for the assembly and activation of the MsmClpP complex.