ClpP: A structurally dynamic protease regulated by AAA+ proteins

Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
Journal of Structural Biology (Impact Factor: 3.23). 05/2012; 179(2):202-10. DOI: 10.1016/j.jsb.2012.05.003
Source: PubMed


Proteolysis is an important process for many aspects of bacterial physiology. Clp proteases carry out a large proportion of protein degradation in bacteria. These enzymes assemble in complexes that combine the protease ClpP and the unfoldase, ClpA or ClpX. ClpP oligomerizes as two stacked heptameric rings enclosing a central chamber containing the proteolytic sites. ClpX and ClpA assemble into hexameric rings that bind both axial surfaces of the ClpP tetradecamer forming a barrel-like complex. ClpP requires association with ClpA or ClpX to unfold and thread protein substrates through the axial pore into the inner chamber where degradation occurs. A gating mechanism regulated by the ATPase exists at the entry of the ClpP axial pore and involves the N-terminal regions of the ClpP protomers. These gating motifs are located at the axial regions of the tetradecamer but in most crystal structures they are not visible. We also lack structural information about the ClpAP or ClpXP complexes. Therefore, the structural details of how the axial gate in ClpP is regulated by the ATPases are unknown. Here, we review our current understanding of the conformational changes that ClpA or ClpX induce in ClpP to open the axial gate and increase substrate accessibility into the degradation chamber. Most of this knowledge comes from the recent crystal structures of ClpP in complex with acyldepsipeptides (ADEP) antibiotics. These small molecules are providing new insights into the gating mechanism of this protease because they imitate the interaction of ClpA/ClpX with ClpP and activate its protease activity.

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    • "Although no evidence exists to directly connect protein import and the protease, the fact that membrane-bound Hsp93/ ClpC appears to be occupied by ClpP raises the intriguing possibility that the Clp system could function as part of a quality control system at the TIC complex in addition to aiding in membrane transport (Fig. 6b) [187]. The Clp/Hsp100 chaperones (e.g., ClpC) function in cooperation with the Clp proteases (ClpP) to constitute a major component of the proteolytic machinery in a wide array of microbes and organelles, including plastids [188] [189] [190] [191]. Clp/Hsp100 chaperones select substrates and serve as molecular unfoldases to feed polypeptides into the ClpP proteolytic chamber for degradation. "
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