Abstract
The caseinolytic protease proteolytic subunit (ClpP) is a serine protease playing an important role in proteostasis of eukaryotic organelles and prokaryotic cells. Alteration of ClpP function has been proved to affect the virulence and infectivity of a number of pathogens. Increased bacterial resistance to antibiotics has become a global problem and new classes of antibiotics with novel mechanisms of action are needed. In this regard, ClpP has emerged as an attractive and potentially viable option to tackle pathogen fitness without suffering cross-resistance to established antibiotic classes and, when not an essential target, without causing an evolutionary selection pressure. This opens a greater window of opportunity for the host immune system to clear the infection by itself or by co-administration with commonly prescribed antibiotics. A comprehensive overview of the function, regulation and structure of ClpP across the different organisms is given. Discussion about mechanism of action of this protease in bacterial pathogenesis and human diseases are outlined, focusing on the compounds developed in order to target the activation or inhibition of ClpP.
Highlights
The caseinolytic protease proteolytic subunit (ClpP) is a serine protease playing an important role in proteostasis of eukaryotic organelles and prokaryotic cells
A protease found in all three domains of life is 20S peptidase, which associates with different AAA+ unfoldases such as Rpt1-Rpt6 ring of the 26S proteasome, proteasome-activating nucleotidase (Pan) and Mycobacterium proteasome-associated ATPase (Mpa) [4,5]
ClpP is well characterized in many species, and it is always involved in the proteolysis of defective anedvemryissfpoelcdieesd
Summary
In every domain of life, cells and organelles are full of proteins, many of which are intrinsically disordered or in the process of folding [1]. Instead, selected proteins in these intracellular environments are arrested, unfolded and degraded by proteolytic machines These specific enzymes belong to the ATPases associated with diverse cellular activities (AAA+) superfamily, due to the presence of an AAA+ unfoldase partner in charge of the recognition of the desired substrates and the ATP-dependent mechanical unfolding of the targeted protein before its translocation to the proteolytic active site [2,3]. These proteolytic machines, enable the cell to keep proteostasis and to alter the protein levels to adapt to changing environments. For an in-depth comparison of ClpP and proteasome, readers are referred to the review published in by Liu et al in 2014 [48]
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