ATP-dependent Clp protease proteolytic subunit 2 (ClpP2)

ATP-dependent Clp protease proteolytic subunit 2 (ClpP2) is an essential serine protease in Mycobacterium tuberculosis (Mtb) that forms a functional heterotetradecameric complex with its partner, ClpP1 [UniProt P9WPC5; Akopian et al., 2012]. This ClpP1P2 complex is a central component of the bacterial protein quality control machinery, responsible for the degradation of misfolded, damaged, or regulatory proteins [Akopian et al., 2012; Ollinger et al., 2012]. Unlike most bacteria that possess a single ClpP isoform, Mtb requires the coordinated action of both ClpP1 and ClpP2 for survival, making the complex an attractive and specific target for antitubercular therapy [UniProt P9WPC5; Famulla et al., 2016]. The complex is regulated by AAA+ chaperones like ClpC1 and ClpX, which recognize and unfold substrates for delivery into the proteolytic chamber [Akopian et al., 2012]. Targeting ClpP2 has emerged as a potent strategy against both active and dormant Mtb. Small molecules such as acyldepsipeptides (ADEPs) bind to ClpP2 and allosterically activate the protease, causing it to degrade essential proteins in an uncontrolled manner, which leads to rapid bacterial cell death [Famulla et al., 2016; Brotz-Oesterhelt et al., 2005]. Conversely, inhibitors like bortezomib and various beta-lactones bind to the active sites of the ClpP1P2 complex to block its essential proteolytic function [Moreno-Cid et al., 2014; Compton et al., 2013]. Because the Mtb ClpP1P2 complex is structurally distinct from the human 26S proteasome and human mitochondrial ClpP, it offers a window for selective toxicity, although potential cross-reactivity remains a consideration in drug design [Compton et al., 2013; Schmitz et al., 2014].

Other names

Caseinolytic protease P2Rv2460cMtb ClpP2ClpP2 protease

Inhibition of the proteolytic activity of the ClpP1P2 complex or allosteric dysregulation leading to uncontrolled proteolysis of essential proteins [Famulla et al., 2016; Brotz-Oesterhelt et al., 2005; Moreno-Cid et al., 2014].