Affinage

CLPP

ATP-dependent Clp protease proteolytic subunit, mitochondrial · UniProt Q16740

Length
277 aa
Mass
30.2 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLPP is a mitochondrial matrix serine protease that assembles as a tetradecameric barrel (two stacked heptameric rings) and serves as the proteolytic core of the ATP-dependent ClpXP complex, where ClpX hexamers dock via IGF-loop motifs to allosterically open N-terminal axial pores and translocate substrates for processive degradation (PMID:15522782, PMID:15064753, PMID:20416323, PMID:35245501). CLPP cooperates with LONP1 to degrade a broad substrate repertoire encompassing OXPHOS subunits, TCA cycle enzymes, and other mitochondrial metabolic proteins, and its loss causes mtDNA instability leading to cytosolic mtDNA release and cGAS-STING-dependent type I interferon signaling (PMID:33637676, PMID:33731338, PMID:26058080). Small-molecule activators—imipridones, ADEPs, and structurally distinct compounds—bind hydrophobic pockets at subunit interfaces to mimic ClpX docking and trigger uncontrolled proteolysis of respiratory chain components, selectively killing cancer cells through OXPHOS collapse and apoptosis (PMID:31056398, PMID:30126533, PMID:37923710). Biallelic CLPP mutations cause Perrault syndrome type 3 by disrupting either the hydrophobic ClpX-docking pocket or the catalytic active site (PMID:30150665).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Establishing that hClpP is a mitochondrial matrix protease with a cleavable targeting sequence resolved its subcellular localization and set the stage for understanding its role in mitochondrial protein quality control.

    Evidence Pulse-chase immunoprecipitation, cell-free mitochondrial import assay, and confocal immunofluorescence co-localization with Hsp60 in human cells

    PMID:9512494

    Open questions at the time
    • Endogenous substrates in the matrix were unknown
    • Whether hClpP required a cognate ATPase partner was not yet established
  2. 2004 High

    Structural and biochemical studies revealed the tetradecameric barrel architecture, identified N-terminal gating loops and the ClpX IGF-loop docking mechanism, and showed that ClpX–ClpP affinity is dynamically regulated during substrate processing, establishing the core operating principles of the ClpXP machine.

    Evidence X-ray crystallography of hClpP at 2.1 Å with mutagenesis; biochemical binding/activity assays with ClpX IGF-loop and sensor-II mutations; EM visualization of hybrid ClpXAP complexes

    PMID:15037252 PMID:15064753 PMID:15522782

    Open questions at the time
    • Structural basis of the ClpX–ClpP interface at atomic resolution was not yet available
    • Substrate identity for human ClpXP was unknown
  3. 2008 High

    Deletion of N-terminal gating residues converted ClpP into an ATPase-independent protease capable of processive degradation, demonstrating that the axial pore is the principal barrier to substrate entry and that the barrel itself determines product size.

    Evidence N-terminal deletion mutagenesis of E. coli ClpP with in vitro protease assays and product size analysis

    PMID:18468623 PMID:19038348

    Open questions at the time
    • Whether human ClpP N-terminal gating behaved identically was not tested
    • Regulation of pore opening in vivo remained unclear
  4. 2007 High

    An RNAi screen in C. elegans identified clpp-1 as essential for mitochondrial unfolded protein response (UPRmt) signaling, linking ClpP protease activity to a retrograde stress signaling pathway.

    Evidence Genome-wide RNAi screen; DVE-1 relocalization and chaperone reporter assays in C. elegans

    PMID:17925224

    Open questions at the time
    • Whether this role was conserved in mammals was untested
    • The signal peptide generated by ClpP for UPRmt was not identified
  5. 2010 High

    Biochemical dissection showed that ClpX binding relieves inhibitory interactions at the ClpP channel, stimulating cleavage of larger peptides even without ATP hydrolysis, establishing that allosteric pore gating—not just substrate delivery—is a key function of the ATPase.

    Evidence In vitro peptide cleavage and active-site modification assays with ClpP channel variant mutagenesis

    PMID:20416323

    Open questions at the time
    • Structural visualization of the open vs closed pore states was lacking
    • How gating relates to substrate selectivity in vivo was unknown
  6. 2015 High

    Two convergent discoveries revealed that ADEP small molecules and ClpX activate ClpP through the same allosteric mechanism at the hydrophobic pocket, and that CLPP interacts with respiratory chain and metabolic enzymes whose degradation upon CLPP knockdown selectively kills leukemic cells.

    Evidence Activity-based profiling, NMR, and biochemical assays for ADEP/ClpX allostery; Co-IP/MS identification of CLPP-interacting proteins plus shRNA screen in AML cells

    PMID:25695750 PMID:26058080

    Open questions at the time
    • Structural basis for ADEP–human ClpP interaction was not yet resolved
    • Whether CLPP activation could be exploited therapeutically in solid tumors was untested
  7. 2016 High

    Mammalian CLPP was shown to be dispensable for UPRmt signaling, overturning the C. elegans paradigm; separately, CLPP knockout mice displayed increased energy expenditure and resistance to diet-induced obesity, revealing metabolic regulatory functions.

    Evidence Double knockout DARS2/CLPP mouse model with UPRmt marker analysis; ClpP-null mouse metabolic phenotyping and high-fat diet challenge

    PMID:27154400 PMID:29420235

    Open questions at the time
    • Tissue-specific roles of CLPP in metabolic regulation were not fully delineated
    • Molecular substrates driving the lean phenotype were unidentified
  8. 2018 High

    Biochemical characterization of Perrault syndrome mutations mapped disease mechanisms to two functional classes—hydrophobic pocket mutations disrupting ClpX docking and active-site-adjacent mutations abolishing both catalysis and docking—establishing genotype–mechanism correlations for this Mendelian disorder.

    Evidence Recombinant mutant CLPP oligomerization, ClpX-docking, peptidase, and protein substrate turnover assays

    PMID:30150665

    Open questions at the time
    • How partial loss of ClpXP activity leads specifically to ovarian and auditory phenotypes was unexplained
    • Patient-derived cell models were not employed
  9. 2019 High

    Identification of imipridones (ONC201 and analogues) as direct ClpP-binding activators provided a chemically tractable scaffold for cancer therapy; structural and genetic evidence confirmed that ClpP is the functional target mediating OXPHOS collapse and cancer cell death.

    Evidence X-ray crystallography of imipridone–ClpP complex; affinity chromatography/MS target identification; siRNA knockdown rescue; cellular OXPHOS and viability assays

    PMID:31021596 PMID:31056398

    Open questions at the time
    • Clinical efficacy in patients was not yet demonstrated
    • Whether resistance mechanisms could bypass ClpP activation was unknown
  10. 2019 High

    α-Synuclein was identified as a direct ClpP interactor that suppresses its peptidase activity and promotes its insolubility, linking ClpP dysfunction to Parkinson's disease pathology; ClpP overexpression rescued neuronal damage.

    Evidence Co-immunoprecipitation; in vitro ClpP peptidase assay with α-synuclein; viral ClpP overexpression rescue in α-synuclein A53T mice and iPSC-derived neurons

    PMID:30877431

    Open questions at the time
    • Whether α-synuclein inhibits ClpP by direct active-site occlusion or allosteric mechanism was unresolved
    • Whether ClpP overexpression is neuroprotective in other PD models was untested
  11. 2021 High

    CLPP loss was shown to cause mtDNA instability and cytosolic release, activating cGAS-STING-dependent type I IFN signaling, establishing an innate immune consequence of mitochondrial protease deficiency; CLPP and LONP1 were found to share an extensive substrate pool.

    Evidence CLPP-null mouse model with genetic/pharmacological cGAS-STING inhibition and mtDNA depletion; APEX proximity proteomics for CLPP/LONP1 substrate overlap

    PMID:33637676 PMID:33731338

    Open questions at the time
    • Whether cGAS-STING activation contributes to Perrault syndrome pathology was untested
    • The mechanism by which CLPP loss destabilizes mtDNA packaging was unknown
  12. 2022 High

    Cryo-EM structures of ClpP–ATPase complexes and crystal structures of next-generation activators (ZK53, ZG111, imipridone derivatives) defined the structural basis for allosteric activation and substrate cleavage preferences, and demonstrated in vivo anti-tumor efficacy across multiple cancer models.

    Evidence Cryo-EM of ClpP–ATPase complexes; crystal structures of ZK53/ClpP and activator/ClpP complexes; N-terminome profiling; xenograft and PDX mouse models

    PMID:35245501 PMID:35905743 PMID:36586405 PMID:37923710

    Open questions at the time
    • Full-length human ClpXP holoenyzme structure at high resolution is still lacking
    • In vivo substrate hierarchy during pharmacological activation is not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the identity of the peptide signals generated by ClpP that communicate mitochondrial stress to the nucleus, the tissue-specific substrate repertoire explaining Perrault syndrome's organ selectivity, and the structural basis for selectivity among chemically diverse ClpP activator scaffolds in clinical settings.
  • Retrograde signaling peptides produced by ClpP remain unidentified
  • Tissue-specific ClpXP substrate profiles have not been mapped
  • Resistance mechanisms to ClpP activators in tumors are unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 5
Localization
GO:0005739 mitochondrion 6
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
CLPXLONP1SHMT2SNCA
Complex memberships
ClpXP

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Human mitochondrial CLPP (hClpP) is synthesized as a precursor with an N-terminal mitochondrial targeting sequence (~56 residues) that is cleaved upon import into mitochondria in a membrane-potential-dependent manner; mature hClpP localizes to the mitochondrial matrix and co-localizes with Hsp60. Pulse-chase immunoprecipitation, cell-free mitochondrial import assay, confocal immunofluorescence co-localization with Hsp60 The Biochemical journal High 9512494
2004 Crystal structure of human mitochondrial ClpP (hClpP) at 2.1 Å shows two heptameric rings enclosing a proteolytic chamber; N-terminal residues (8–16) form a mobile loop essential for ClpX-mediated protein and peptide degradation, and residues at the start of the unique 28-aa C-terminal domain affect heptamer assembly and stability. X-ray crystallography at 2.1 Å; site-directed mutagenesis and deletion of N-terminal loop/C-terminal domain with functional activity assays Journal of structural biology High 15522782
2004 ClpX–ClpP affinity is dynamically regulated during substrate processing: it varies with the protein-processing task of ClpX and with catalytic engagement of ClpP active sites; functional communication depends on ClpX ATPase activity transmitted through IGF loops, and a conserved arginine in the sensor II helix of ClpX links nucleotide state to ClpP binding. Biochemical binding and activity assays, mutagenesis of ClpX IGF loops and sensor II helix, ATP hydrolysis measurements Nature structural & molecular biology High 15064753
2005 X-ray structure of S. pneumoniae ClpP(A153P) at 2.5 Å reveals that the handle region mediates ring–ring dimerization with unusual plasticity, and that flexible N-terminal loops lining the axial pores are essential determinants for ClpXP and ClpAP complex formation; truncation or mutation of loop residues impairs complex formation and uncouples ATPase–protease activity. X-ray crystallography at 2.5 Å; biochemical mutagenesis of N-terminal loop residues; ClpXP/ClpAP complex formation and activity assays The Journal of biological chemistry High 15701650
2004 ClpA and ClpX hexamers bind simultaneously to opposite ends of the ClpP tetradecamer to form functional hybrid ClpXAP complexes that can independently translocate distinct substrate classes into ClpP without redistribution of the ATPase subunits. Electron microscopy visualization of substrate translocation into proteolytically inactive ClpP; in vitro reconstitution of hybrid complexes Journal of structural biology High 15037252
2007 In C. elegans, the mitochondrial matrix protease clpp-1 (ClpP homolog) is required for signaling the mitochondrial unfolded protein response (UPRmt): reduced clpp-1 activity attenuates nuclear redistribution of DVE-1, DVE-1/UBL-5 complex formation, and downstream chaperone gene induction. Genome-wide RNAi screen; RNAi knockdown of clpp-1 with reporter assays; ChIP showing DVE-1 binding to chaperone promoters Developmental cell High 17925224
2015 Human mitochondrial CLPP interacts with respiratory chain proteins and metabolic enzymes; knockdown of CLPP in AML leukemic cells inhibits oxidative phosphorylation and mitochondrial metabolism, selectively killing leukemic cells with elevated CLPP expression. shRNA screen; Co-immunoprecipitation/MS identification of CLPP-interacting respiratory chain and metabolic proteins; genetic and chemical CLPP inhibition with OCR measurements Cancer cell High 26058080
2019 Imipridone compounds (ONC201 and analogues) bind human mitochondrial ClpP non-covalently in its hydrophobic pocket, activate proteolytic activity, cause selective degradation of respiratory chain protein substrates, and disrupt mitochondrial structure and function to kill cancer cells. Biochemical ClpP activity assays; X-ray crystallography of imipridone–ClpP complex; affinity chromatography/drug competition; siRNA knockdown rescue experiments Cancer cell High 31056398
2019 ONC201 and TR analogue compounds directly bind human mitochondrial ClpP (identified by affinity chromatography/MS) and potently activate its peptidase activity in a dose- and time-dependent manner; siRNA knockdown of ClpP reduces cellular responses to these compounds including CHOP induction and loss of TFAM/TUFM. Affinity chromatography with immobilized TR compounds and MS identification; recombinant ClpP peptidase activity assay; siRNA knockdown with cellular phenotypic readouts ACS chemical biology High 31021596
2018 ADEP analogues interact tightly with human mitochondrial ClpP (HsClpP), causing non-specific degradation of model substrates; ADEP–HsClpP co-crystal structure shows binding at hydrophobic pockets formed by two neighboring subunits, with HsClpP in the compact conformation; ADEP-mediated dysregulation activates intrinsic, caspase-dependent apoptosis. X-ray co-crystallography; in vitro peptidase activity assays; caspase activation assays; apoptosis assays Cell chemical biology High 30126533
2015 Both AAA+ chaperones (ClpX) and ADEP small molecules activate ClpP through allosteric conformational control of the ClpP barrel; ADEP cooperatively binds the hydrophobic pocket, opens the axial pore, and directly stimulates active-site residues; substoichiometric ADEP potently prevents ClpX binding to ClpP. Chemical probes (activity-based profiling); NMR; biochemical binding and activity assays; ADEP-ClpP interaction studies Nature communications High 25695750
2010 ClpX binding stimulates ClpP cleavage of peptides larger than a few amino acids and enhances active-site modification; this stimulation requires ATP binding but not hydrolysis; channel loop and helix A residues of ClpP gate substrate entry, with ClpX binding relieving inhibitory interactions to allow translocation. In vitro peptide cleavage assays; active-site modification assays; ClpP channel variant mutagenesis with ClpXP translocation assays Journal of molecular biology High 20416323
2008 Removal of 10–17 N-terminal residues of mature E. coli ClpP allows ATPase-independent, processive degradation of unfolded proteins; the product size distribution of ΔN-ClpP is identical to ClpAP and ClpXP, indicating ATPases do not determine product size distribution. N-terminal deletion mutagenesis; in vitro protease activity assays on model unfolded substrate; product size analysis Journal of structural biology High 19038348
2008 Crystal structures of Helicobacter pylori ClpP in apo form and in complex with product peptides show that peptides bind in antiparallel β-strand fashion at the active site, pointing to the adjacent active site; this explains broad substrate specificity, product inhibition, and processive degradation. X-ray crystallography of ClpP–peptide product complexes Journal of molecular biology High 18468623
2011 ADEP antibiotics activate bacterial ClpP to degrade the essential cell division protein FtsZ in vivo and in vitro, preventing Z-ring assembly and inhibiting septum formation; ADEP switches ClpP from a regulated to an uncontrolled protease. In vivo and in vitro degradation assays; fluorescence microscopy of cell division protein localization; genetic confirmation requiring ClpP Proceedings of the National Academy of Sciences of the United States of America High 21969594
2019 Bortezomib binds the ClpP active-site serine (mimicking a peptide substrate) and induces allosteric activation of the entire tetradecameric ClpP complex; the activated conformation also exhibits higher affinity for cognate unfoldase ClpX, suggesting a universal allosteric mechanism for substrate-induced ClpP activation. X-ray crystallography; solid- and solution-state NMR; molecular dynamics simulations; isothermal titration calorimetry; biochemical activity assays Science advances High 31517045
2018 A small molecule D9 acts as a potent, species-selective activator of human ClpP by mimicking the natural chaperone ClpX, interacting with a unique YYW aromatic amino acid network in hClpP that is absent in bacterial homologues; mutagenesis of this motif abolishes activation. Structure-activity relationship studies; mutational analysis of YYW motif; structural studies; species selectivity assays Angewandte Chemie (International ed. in English) High 30129683
2018 NMR, cryo-EM, and mutagenesis of S. aureus ClpP reveal that a hydrophobic site in the N-terminal domain acts as a conformational switch: mutation at this site unfolds N-terminal domains, abolishes activity, and creates a split-ring conformation with 20-Å pores in the complex side; ADEP binding to the hydrophobic pocket restores the extended active conformation. Methyl-TROSY NMR; cryo-EM; molecular dynamics simulations; biochemical activity assays; mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 29941580
2013 β-sultam compounds inhibit ClpP via two mechanisms: (1) substoichiometric binding induces disassembly of the active tetradecameric complex into inactive heptamers; (2) active-site serine undergoes covalent dehydroalanine formation through sulfonylation followed by elimination, obliterating the catalytic triad; confirmed by crystallography and mass spectrometry. X-ray crystallography; mass spectrometry; activity-based protein profiling in S. aureus cells; biochemical assembly assays Journal of the American Chemical Society High 24106749
2015 Human mitochondrial ClpP, bacterial E. coli, and S. aureus ClpP exhibit defined preferences for certain amino acids at P1, P2, and P3 positions in fluorogenic substrate assays; however, during ClpXP-mediated degradation of endogenous substrates this specificity is attenuated, and the barrel architecture provides high local substrate concentrations enabling diverse cleavage. Fluorogenic substrate library profiling; MS analysis of ClpXP degradation products; customized substrates with unnatural amino acids; Perrault syndrome ClpP mutant activity profiling ACS chemical biology High 26606371
2016 Mammalian CLPP is neither required for, nor regulates the UPRmt in mammals: deletion of CLPP in DARS2-deficient hearts with robust UPRmt induction does not abolish UPRmt signaling, but instead alleviates severe mitochondrial cardiomyopathy and increases de novo synthesis of OXPHOS subunits. Genetic double knockout mouse model (DARS2/CLPP); OXPHOS subunit synthesis measurement; mitochondrial respiration assays; UPRmt marker analysis EMBO reports High 27154400
2019 α-Synuclein (αSyn) wild-type and A53T mutant physically interact with mitochondrial ClpP and suppress its peptidase activity; this binding shifts ClpP from soluble to insoluble cellular fraction, reduces ClpP levels in dopaminergic neurons, and causes mitochondrial oxidative damage; viral overexpression of ClpP rescues neuronal pathology. Co-immunoprecipitation; in vitro ClpP peptidase activity assay with αSyn; fractionation; viral ClpP overexpression in αSyn A53T mice with behavioral readouts Acta neuropathologica High 30877431
2021 Loss of mitochondrial CLPP protease causes mtDNA instability and packaging alterations that lead to cytosolic mtDNA release, activating the cGAS-STING pathway and constitutive type I IFN signaling; pharmacological or genetic depletion of mtDNA or inhibition of cGAS-STING reduces antiviral gene expression in CLPP-null cells. CLPP-null mouse model; genetic and pharmacological cGAS-STING inhibition; mtDNA depletion; antiviral resistance assays; IFN reporter assays Journal of immunology High 33731338
2021 Human mitochondrial CLPP and LONP1 cooperate to degrade shared substrates including SHMT2; both proteases share an extensive substrate pool encompassing OXPHOS, TCA cycle, fatty acid metabolism, and amino acid metabolism components, identified by APEX-mediated proximity biotinylation proteomics. Engineered peroxidase (APEX) proximity biotinylation proteomics; siRNA co-depletion of LONP1 and ClpP; cell viability and SHMT2 inhibitor sensitivity assays Oncogenesis High 33637676
2022 Cryo-EM structures of ClpP-ATPase complexes reveal how a hexameric ATPase and tetradecameric ClpP work together; structures define the mechanism of substrate unfolding and translocation and reveal allosteric control of ClpP by small molecules and gain/loss-of-function mutations. Cryo-EM structural determination of ClpP-ATPase complexes The Journal of biological chemistry High 35245501
2022 Crystal structures of imipridone-derived ClpP activators in complex with human mitochondrial ClpP reveal enhanced binding due to greater shape/charge complementarity with surface hydrophobic pockets; N-terminome profiling of cancer cells identifies preferred structural motifs for cleavage by compound-activated ClpP. X-ray crystallography of compound-ClpP complexes; N-terminome profiling by MS; biochemical binding affinity assays Structure (London, England : 1993) High 36586405
2020 ADEP-activated ClpP alone (without any Clp-ATPase) unfolds and degrades the N-terminal domain of FtsZ in vitro; nucleotide binding to FtsZ stabilizes its fold and prevents this degradation; at elevated ADEP concentrations the FtsZ C-terminus is additionally targeted. In vitro ADEP-ClpP degradation assays with purified FtsZ; nucleotide stabilization rescue assay; N-terminal vs C-terminal domain degradation analysis mBio High 32605984
2016 A gain-of-function S. aureus ClpP mutant (Y63A) degrades FtsZ in vivo and inhibits bacterial growth; the crystal structure of Y63A ClpP and the cryo-EM structure of N42A/Y63A ClpP reveal an enlarged entrance pore as the structural basis for ATPase-independent proteolytic activation; ADEPs mimic the same activation mechanism. Crystal structure and cryo-EM of ClpP gain-of-function mutants; in vivo FtsZ degradation assay; whole-proteome MS of degraded proteins ACS chemical biology High 27171654
2019 IGF-motif loops of ClpX are required for ClpP docking; ATP/ATPγS binding changes ClpX ring conformation, bringing IGF loops closer together for multivalent ClpP contact; deletion of one or two IGF loops markedly accelerates ClpXP complex dissociation and reduces proteolytic processivity. Single-chain ClpX pseudohexamer IGF loop deletion mutagenesis; ClpXP association/dissociation kinetics; ATP-dependent degradation assays Protein science High 30767302
2015 Knockdown of CLPP (~70%) in C2C12 muscle cells reduces mitochondrial respiration, alters mitochondrial morphology, changes expression of fission protein Drp1, blunts UPRmt induction, increases ROS, decreases membrane potential, impairs myoblast differentiation, reduces cell proliferation, and elevates eIF2α phosphorylation. siRNA and lentiviral shRNA stable knockdown; Seahorse respirometry; ROS measurement; membrane potential assay; differentiation and proliferation assays; immunoblotting Free radical biology & medicine Medium 26721594
2018 ClpP knockout mice exhibit reduced adiposity, improved insulin sensitivity, increased whole-body energy expenditure, and selective upregulation of mitochondrial biogenesis markers in white adipose tissue; ClpP-/- mice are protected from diet-induced obesity and insulin resistance, indicating ClpP modulates mitochondrial biogenesis and metabolic signaling. ClpP knockout mouse model; metabolic phenotyping; high-fat diet challenge; energy expenditure measurement; WAT proteomic/gene expression analysis EMBO reports High 29420235
2018 CLPP mutations causing Perrault syndrome type 3 cluster in two functional regions: those near the hydrophobic pocket (T145P, C147S) that disrupt ClpX-docking with variable severity, and those adjacent to the active site (Y229D) that inhibit peptidase activity and unexpectedly also prevent ClpX docking, blocking both peptide and protein substrate turnover. Biochemical characterization of recombinant mutant CLPP proteins: oligomerization assays, ClpX-docking assays, peptidase activity assays, protein substrate turnover assays Scientific reports High 30150665
2022 ZK53, a selective human ClpP activator structurally distinct from ADEPs and imipridones, binds ClpP via π-π stacking as revealed by crystal structure; it causes ClpP-dependent decrease in electron transport chain components, reduces oxidative phosphorylation and ATP production, and activates ATM-mediated DNA damage response triggering cell cycle arrest in lung tumor cells. Crystal structure of ZK53/ClpP complex; ClpP-dependent rescue experiments; Seahorse OXPHOS assay; ATM pathway and cell cycle analysis; xenograft and autochthonous mouse models Nature communications High 37923710
2022 ZG111, a ClpP activator identified by high-throughput screening, binds ClpP and promotes ClpP-mediated degradation of respiratory chain complexes, activating the JNK/c-Jun pathway and inducing ER stress response to cause PDAC cell growth arrest; efficacy confirmed in cell-line-derived and patient-derived xenograft mouse models. HTS; biochemical ClpP binding and activation assays; respiratory chain complex degradation; JNK/c-Jun pathway analysis; ER stress markers; PDX mouse models Cell chemical biology High 35905743
2019 Boron-containing α-aminoboronic acid peptidomimetics are the first inhibitors of human mitochondrial ClpXP, functioning as covalent inhibitors that prevent ClpP-mediated degradation of misfolded proteins. De novo virtual library design; biochemical ClpXP inhibition assays; cellular viability assays Journal of medicinal chemistry Medium 31187989
2008 Frataxin deficiency in mouse heart causes progressive upregulation of both Lon and ClpP proteases with increased proteolytic activity; this correlates with progressive loss of mitochondrial Fe-S proteins, suggesting Fe-S proteins are substrates of these proteases during Friedreich ataxia progression. Western blotting for Lon and ClpP protein levels; proteolytic activity assays; measurement of Fe-S protein levels in frataxin-deficient mouse hearts at progressive disease stages The FEBS journal Medium 19154341
2019 ClpP overexpression reduces αSyn-induced mitochondrial oxidative stress by enhancing levels of SOD2, and suppresses αSyn S129 phosphorylation accumulation while promoting neuronal morphology in neurons derived from PD patient iPS cells. Viral ClpP overexpression in iPSC-derived neurons; SOD2 immunoblotting; αSyn S129 phosphorylation assay; neuronal morphology analysis Acta neuropathologica Medium 30877431

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Developmental cell 495 17925224
2019 Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer cell 294 31056398
2015 Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer cell 292 26058080
2003 Alternative roles of ClpX and ClpP in Staphylococcus aureus stress tolerance and virulence. Molecular microbiology 264 12791139
2007 Clp ATPases and ClpP proteolytic complexes regulate vital biological processes in low GC, Gram-positive bacteria. Molecular microbiology 234 17302811
2008 CLB19, a pentatricopeptide repeat protein required for editing of rpoA and clpP chloroplast transcripts. The Plant journal : for cell and molecular biology 212 18657233
2000 The ClpP serine protease is essential for the intracellular parasitism and virulence of Listeria monocytogenes. Molecular microbiology 212 10760131
1998 ClpP of Bacillus subtilis is required for competence development, motility, degradative enzyme synthesis, growth at high temperature and sporulation. Molecular microbiology 190 9535081
2006 Global regulatory impact of ClpP protease of Staphylococcus aureus on regulons involved in virulence, oxidative stress response, autolysis, and DNA repair. Journal of bacteriology 179 16885446
2019 Mitochondrial Protease ClpP is a Target for the Anticancer Compounds ONC201 and Related Analogues. ACS chemical biology 156 31021596
2011 Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proceedings of the National Academy of Sciences of the United States of America 147 21969594
2008 Complete plastid genome sequence of the chickpea (Cicer arietinum) and the phylogenetic distribution of rps12 and clpP intron losses among legumes (Leguminosae). Molecular phylogenetics and evolution 141 18638561
2004 Communication between ClpX and ClpP during substrate processing and degradation. Nature structural & molecular biology 124 15064753
2002 Global transcriptional analysis of clpP mutations of type 2 Streptococcus pneumoniae and their effects on physiology and virulence. Journal of bacteriology 121 12057945
2018 The Role of ClpP Protease in Bacterial Pathogenesis and Human Diseases. ACS chemical biology 117 29775273
2011 walK and clpP mutations confer reduced vancomycin susceptibility in Staphylococcus aureus. Antimicrobial agents and chemotherapy 113 21628539
1999 ClpP participates in the degradation of misfolded protein in Lactococcus lactis. Molecular microbiology 113 9987112
2020 Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy. Cell death & disease 111 33037181
2002 Regulation and Physiological Significance of ClpC and ClpP in Streptococcus mutans. Journal of bacteriology 109 12399506
2015 AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control. Nature communications 107 25695750
2005 The ClpP double ring tetradecameric protease exhibits plastic ring-ring interactions, and the N termini of its subunits form flexible loops that are essential for ClpXP and ClpAP complex formation. The Journal of biological chemistry 102 15701650
2016 Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt. EMBO reports 101 27154400
1999 Effects of DksA and ClpP protease on sigma S production and virulence in Salmonella typhimurium. Molecular microbiology 100 10540290
2004 Crystallography and mutagenesis point to an essential role for the N-terminus of human mitochondrial ClpP. Journal of structural biology 99 15522782
2014 Conditional Depletion of the Chlamydomonas Chloroplast ClpP Protease Activates Nuclear Genes Involved in Autophagy and Plastid Protein Quality Control. The Plant cell 98 24879428
1990 The ClpP component of Clp protease is the sigma 32-dependent heat shock protein F21.5. Journal of bacteriology 98 2211522
2013 Trapping and proteomic identification of cellular substrates of the ClpP protease in Staphylococcus aureus. Journal of proteome research 97 23253041
2018 Acyldepsipeptide Analogs Dysregulate Human Mitochondrial ClpP Protease Activity and Cause Apoptotic Cell Death. Cell chemical biology 94 30126533
2003 Global role for ClpP-containing proteases in stationary-phase adaptation of Escherichia coli. Journal of bacteriology 89 12486047
2015 Down-regulation of the mitochondrial matrix peptidase ClpP in muscle cells causes mitochondrial dysfunction and decreases cell proliferation. Free radical biology & medicine 80 26721594
2018 Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance. EMBO reports 76 29420235
2019 Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity. Acta neuropathologica 71 30877431
2007 Role of ClpP in biofilm formation and virulence of Staphylococcus epidermidis. Microbes and infection 71 17890122
2008 Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins. The FEBS journal 69 19154341
2008 Decreased expression of the mitochondrial matrix proteases Lon and ClpP in cells from a patient with hereditary spastic paraplegia (SPG13). Neuroscience 67 18378094
2010 Control of substrate gating and translocation into ClpP by channel residues and ClpX binding. Journal of molecular biology 66 20416323
2007 A Pentatricopeptide repeat protein is required for RNA processing of clpP Pre-mRNA in moss chloroplasts. The Journal of biological chemistry 66 17283080
1999 Signal peptide peptidase- and ClpP-like proteins of Bacillus subtilis required for efficient translocation and processing of secretory proteins. The Journal of biological chemistry 63 10455123
2011 New insights into Staphylococcus aureus stress tolerance and virulence regulation from an analysis of the role of the ClpP protease in the strains Newman, COL, and SA564. Journal of proteome research 57 22112206
2004 The ClpP peptidase is the major determinant of bulk protein turnover in Bacillus subtilis. Journal of bacteriology 57 15317791
1998 A human homologue of Escherichia coli ClpP caseinolytic protease: recombinant expression, intracellular processing and subcellular localization. The Biochemical journal 55 9512494
2022 Recent structural insights into the mechanism of ClpP protease regulation by AAA+ chaperones and small molecules. The Journal of biological chemistry 54 35245501
2021 LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival. Oncogenesis 54 33637676
2018 Selective Activation of Human Caseinolytic Protease P (ClpP). Angewandte Chemie (International ed. in English) 53 30129683
2009 ClpP of Streptococcus mutans differentially regulates expression of genomic islands, mutacin production, and antibiotic tolerance. Journal of bacteriology 52 20038588
1999 ClpA and ClpP remain associated during multiple rounds of ATP-dependent protein degradation by ClpAP protease. Biochemistry 51 10555973
2022 Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma. Cell chemical biology 49 35905743
2018 Reversible inhibition of the ClpP protease via an N-terminal conformational switch. Proceedings of the National Academy of Sciences of the United States of America 49 29941580
2000 Mutations conferring amino acid residue substitutions in the carboxy-terminal domain of RNA polymerase alpha can suppress clpX and clpP with respect to developmentally regulated transcription in Bacillus subtilis. Molecular microbiology 49 10972808
2013 The ClpP protease is required for the stress tolerance and biofilm formation in Actinobacillus pleuropneumoniae. PloS one 48 23326465
2004 ClpA and ClpX ATPases bind simultaneously to opposite ends of ClpP peptidase to form active hybrid complexes. Journal of structural biology 48 15037252
2021 Substrates and interactors of the ClpP protease in the mitochondria. Current opinion in chemical biology 47 34446368
2019 Chemical Modulation of Human Mitochondrial ClpP: Potential Application in Cancer Therapeutics. ACS chemical biology 47 31241890
2021 Loss of Mitochondrial Protease CLPP Activates Type I IFN Responses through the Mitochondrial DNA-cGAS-STING Signaling Axis. Journal of immunology (Baltimore, Md. : 1950) 45 33731338
2019 Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. Science advances 45 31517045
2016 The development of small-molecule modulators for ClpP protease activity. Molecular bioSystems 45 27831584
2017 The ATP-Dependent Protease ClpP Inhibits Biofilm Formation by Regulating Agr and Cell Wall Hydrolase Sle1 in Staphylococcus aureus. Frontiers in cellular and infection microbiology 44 28555174
2013 Disruption of oligomerization and dehydroalanine formation as mechanisms for ClpP protease inhibition. Journal of the American Chemical Society 44 24106749
2008 The structural basis for the activation and peptide recognition of bacterial ClpP. Journal of molecular biology 43 18468623
1998 ClpX and ClpP are essential for the efficient acquisition of genes specifying type IA and IB restriction systems. Molecular microbiology 43 9593294
2019 Senescent Hepatocytes in Decompensated Liver Show Reduced UPRMT and Its Key Player, CLPP, Attenuates Senescence In Vitro. Cellular and molecular gastroenterology and hepatology 41 30878663
2022 Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome. Structure (London, England : 1993) 39 36586405
2006 Construction and characterization of a Lactococcus lactis strain deficient in intracellular ClpP and extracellular HtrA proteases. Microbiology (Reading, England) 39 16946256
2023 Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma. Nature communications 38 37923710
2008 Polar localization and compartmentalization of ClpP proteases during growth and sporulation in Bacillus subtilis. Journal of bacteriology 38 18689476
2022 Quercetin Reduces the Virulence of S. aureus by Targeting ClpP to Protect Mice from MRSA-Induced Lethal Pneumonia. Microbiology spectrum 37 35319277
2015 Exome analysis identified a novel missense mutation in the CLPP gene in a consanguineous Saudi family expanding the clinical spectrum of Perrault Syndrome type-3. Journal of the neurological sciences 37 25956234
2008 Turned on for degradation: ATPase-independent degradation by ClpP. Journal of structural biology 37 19038348
2022 Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP. Pharmacology research & perspectives 36 35929764
2019 De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX. Journal of medicinal chemistry 36 31187989
2005 The ClgR protein regulates transcription of the clpP operon in Bifidobacterium breve UCC 2003. Journal of bacteriology 36 16321946
2018 Perrault syndrome type 3 caused by diverse molecular defects in CLPP. Scientific reports 35 30150665
2015 Barrel-shaped ClpP Proteases Display Attenuated Cleavage Specificities. ACS chemical biology 35 26606371
2013 Mycobacterium tuberculosis ClpP proteases are co-transcribed but exhibit different substrate specificities. PloS one 35 23560081
2022 ClpP inhibitors are produced by a widespread family of bacterial gene clusters. Nature microbiology 34 35246663
2020 ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis. BMC microbiology 34 32033530
1997 Identification of an unusual intein in chloroplast ClpP protease of Chlamydomonas eugametos. The Journal of biological chemistry 34 9115246
2022 Cellular functions of the ClpP protease impacting bacterial virulence. Frontiers in molecular biosciences 33 36533084
2022 Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice. Journal of hepatology 32 35421426
2016 Characterization of Gain-of-Function Mutant Provides New Insights into ClpP Structure. ACS chemical biology 31 27171654
2008 Helicobacter pylori mutants defective in the clpP ATP-dependant protease and the chaperone clpA display reduced macrophage and murine survival. Microbial pathogenesis 31 18992803
2002 Overexpression of the clpP 5'-untranslated region in a chimeric context causes a mutant phenotype, suggesting competition for a clpP-specific RNA maturation factor in tobacco chloroplasts. Plant physiology 31 12177472
2020 Cell Division Protein FtsZ Is Unfolded for N-Terminal Degradation by Antibiotic-Activated ClpP. mBio 29 32605984
2019 The ADEP Biosynthetic Gene Cluster in Streptomyces hawaiiensis NRRL 15010 Reveals an Accessory clpP Gene as a Novel Antibiotic Resistance Factor. Applied and environmental microbiology 29 31399403
2016 Effect of clpP and clpC deletion on persister cell number in Staphylococcus aureus. Journal of medical microbiology 29 27375177
2019 Roles of the ClpX IGF loops in ClpP association, dissociation, and protein degradation. Protein science : a publication of the Protein Society 28 30767302
2014 A simple fragment of cyclic acyldepsipeptides is necessary and sufficient for ClpP activation and antibacterial activity. Chembiochem : a European journal of chemical biology 28 25212124
2005 Lon and ClpP proteases participate in the physiological disintegration of bacterial inclusion bodies. Journal of biotechnology 28 15967532
2022 Induction of Synthetic Lethality by Activation of Mitochondrial ClpP and Inhibition of HDAC1/2 in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 27 35417530
2019 Role of ClpX and ClpP in Streptococcus suis serotype 2 stress tolerance and virulence. Microbiological research 27 31178057
2020 Global Inventory of ClpP- and ClpX-Regulated Proteins in Staphylococcus aureus. Journal of proteome research 26 33210542
2020 Development of Antibiotics That Dysregulate the Neisserial ClpP Protease. ACS infectious diseases 26 33237740
2003 Role of the Streptococcus agalactiae ClpP serine protease in heat-induced stress defence and growth arrest. Microbiology (Reading, England) 26 12624203
2022 Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis. Cancer research communications 25 36388465
2020 Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo. Journal of medicinal chemistry 25 32031798
2018 Initial Characterization of the Two ClpP Paralogs of Chlamydia trachomatis Suggests Unique Functionality for Each. Journal of bacteriology 25 30396899
2016 Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects. Frontiers in neurology 25 27899912
2013 ClpP deletion causes attenuation of Salmonella Typhimurium virulence through mis-regulation of RpoS and indirect control of CsrA and the SPI genes. Microbiology (Reading, England) 25 23676436
2016 ClpP-deletion impairs the virulence of Legionella pneumophila and the optimal translocation of effector proteins. BMC microbiology 24 27484084
2024 A review of current therapeutics targeting the mitochondrial protease ClpP in diffuse midline glioma, H3 K27-altered. Neuro-oncology 23 37589388