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Last update 23 Jan 2025

ATP-dependent protease ATP-binding subunit ClpC1

Last update 23 Jan 2025

Basic Info

Synonyms

clpC1

Introduction-

Drugs associated with ATP-dependent protease ATP-binding subunit ClpC1

Rufomycin I

Target

ATP-dependent protease ATP-binding subunit ClpC1

Mechanism

ATP-dependent protease ATP-binding subunit ClpC1 inhibitors

Active Org.

University of Illinois

Originator Org.

University of Illinois

Active Indication

Mycobacterium Abscessus Infection [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

UdSBI-4377

Target

ATP-dependent protease ATP-binding subunit ClpC1

Mechanism

ATP-dependent protease ATP-binding subunit ClpC1 inhibitors

Active Org.

Boehringer Ingelheim Ltd.

Originator Org.

Boehringer Ingelheim Ltd.

Active Indication

Mycobacterium Infections

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Metamarin

Target

ATP-dependent protease ATP-binding subunit ClpC1

Mechanism

ATP-dependent protease ATP-binding subunit ClpC1 agonists

Active Org.

The Rockefeller University

Originator Org.

The Rockefeller University

Active Indication

Drug-Resistant Tuberculosis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ATP-dependent protease ATP-binding subunit ClpC1

100 Translational Medicine associated with ATP-dependent protease ATP-binding subunit ClpC1

0 Patents (Medical) associated with ATP-dependent protease ATP-binding subunit ClpC1

Literatures (Medical) associated with ATP-dependent protease ATP-binding subunit ClpC1

01 Jan 2025·Molecular Microbiology

ClpS Directs Degradation of N‐Degron Substrates With Primary Destabilizing Residues in Mycolicibacterium smegmatis

Article

Author: Presloid, Christopher J. ; Kandel, Pratistha ; Schmitz, Karl R. ; Beardslee, Patrick C. ; Anderson, Henry R. ; Swayne, Thomas M. ; Jiang, Jialiu

ABSTRACTDrug‐resistant tuberculosis infections are a major threat to global public health. The essential mycobacterial ClpC1P1P2 protease has received attention as a prospective target for novel antibacterial therapeutics. However, efforts to probe its function in cells are constrained by our limited knowledge of its physiological proteolytic repertoire. Here, we interrogate the role of mycobacterial ClpS in directing N‐degron pathway proteolysis by ClpC1P1P2 in Mycolicibacterium smegmatis. Binding assays demonstrate that mycobacterial ClpS binds canonical primary destabilizing residues (Leu, Phe, Tyr, Trp) with moderate affinity. N‐degron binding restricts the conformational flexibility of a loop adjacent to the ClpS N‐degron binding pocket and strengthens ClpS•ClpC1 binding affinity ~30‐fold, providing a mechanism for cells to prioritize N‐degron proteolysis when substrates are abundant. Proteolytic reporter assays in M. smegmatis confirm degradation of substrates bearing primary N‐degrons, but suggest that secondary N‐degrons are absent in mycobacteria. This work expands our understanding of the mycobacterial N‐degron pathway and identifies ClpS as a critical component for substrate specificity, providing insights that may support the development of improved Clp protease inhibitors.

04 Nov 2024·Plant Physiology

The chloroplast protease system degrades stromal DUF760-1 and DUF760-2 domain-containing proteins at different rates

Article

Author: van Wijk, Klaas J ; Yuan, Bingjian

AbstractThe chloroplast chaperone CLPC1 aids to select, unfold, and deliver hundreds of proteins to the CLP protease for degradation. Through in vivo CLPC1, trapping we previously identified dozens of proteins that are (potential) substrate adaptors or substrates for the CLP chaperone–protease system. In this study, we show that two of these highly trapped proteins, DUF760-1 and DUF760-2, are substrates for the CLP protease in Arabidopsis (Arabidopsis thaliana). Loss-of-function mutants and transgenic plants were created for phenotyping, protein expression, and localization using immunoblotting and confocal microscopy. In planta BiFC, cycloheximide chase assays, and yeast 2-hybrid analyses were conducted to determine protein interactions and protein half-life. Both DUF760 proteins directly interacted with the N-domain of CLPC1 and both were highly enriched in clpc1-1 and clpr2-1 mutants. Accordingly, in vivo cycloheximide chase assays demonstrated that both DUF760 proteins are degraded by the CLP protease. The half-life of DUF760-1 was 4 to 6 h, whereas DUF760-2 was highly unstable and difficult to detect unless CLP proteolysis was inhibited. Null mutants for DUF760-1 and DUF760-2 showed weak but differential pigment phenotypes and differential sensitivity to protein translation inhibitors. This study demonstrates that DUF760-1 and DUF760-2 are substrates of the CLP chaperone–protease system and excellent candidates for the determination of CLP substrate degrons.

01 Jul 2024·Plant, Cell & Environment

Mutant noxy8 exposes functional specificities between the chloroplast chaperones CLPC1 and CLPC2 in the response to organelle stress and plant defence

Article

Author: Izquierdo, Yovanny ; López, Bran ; Pulido, Pablo ; Castresana, Carmen ; Cascón, Tomás ; Zamarreño, Ángel M. ; García‐Mina, José M.

AbstractChloroplast function is essential for growth, development, and plant adaptation to stress. Organelle stress and plant defence responses were examined here using noxy8 (nonresponding to oxylipins 8) from a series of Arabidopsis mutants. The noxy8 mutation was located at the CLPC2 gene, encoding a chloroplast chaperone of the protease complex CLP. Although its CLPC1 paralogue is considered to generate redundancy, our data reveal significant differences distinguishing CLPC2 and CLPC1 functions. As such, clpc1 mutants displayed a major defect in housekeeping chloroplast proteostasis, leading to a pronounced reduction in growth and pigment levels, enhanced accumulation of chloroplast and cytosol chaperones, and resistance to fosmidomycin. Conversely, clpc2 mutants showed severe susceptibility to lincomycin inhibition of chloroplast translation and resistance to Antimycin A inhibition of mitochondrial respiration. In the response to Pseudomonas syringae pv. tomato, clpc2 but not clpc1 mutants were resistant to bacterial infection, showing higher salicylic acid levels, defence gene expression and 9‐LOX pathway activation. Our findings suggest CLPC2 and CLPC1 functional specificity, with a preferential involvement of CLPC1 in housekeeping processes and of CLPC2 in stress responses.

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ATP-dependent protease ATP-binding subunit ClpC1

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