Affinage

CLPP

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

Length
277 aa
Mass
30.2 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLPP is the proteolytic core of the mitochondrial matrix ATP-dependent ClpXP protease, a self-compartmentalizing serine protease that maintains mitochondrial proteostasis and respiratory function (PMID:9512494, PMID:26058080). It is nuclear-encoded as a ~39 kDa precursor that is imported into mitochondria in a membrane-potential-dependent manner and processed by cleavage of its N-terminal targeting sequence to the mature ~32 kDa form, and it has no detectable proteolytic activity in isolation, requiring partner factors for function (PMID:9512494). Catalysis is conferred by association with the AAA+ unfoldase ClpX: ATP binding reorganizes the ClpX ring so that its IGF-motif loops dock into hydrophobic clefts on the ClpP barrel, opening the N-terminal axial gate that otherwise excludes large substrates and allosterically stimulating the catalytic residues, with the ATPase establishing a stable, processive degradation complex rather than dictating product size (PMID:15064753, PMID:20416323, PMID:30767302, PMID:10555973). Activation is fundamentally a conformational switch of the ClpP barrel between compressed/inactive and extended/active states governed by N-terminal gate ordering and electrostatic network reorganization at the entrance pores (PMID:29941580, PMID:31754640, PMID:33232135). Small-molecule agonists — ADEP antibiotics and imipridone/ONC201-class compounds — bind the same hydrophobic pockets used by ClpX and dysregulate human ClpP into ATPase-independent, non-specific degradation that destroys respiratory chain complexes, collapses OXPHOS and ATP production, and triggers intrinsic apoptosis and stress signaling in cancer cells (PMID:30126533, PMID:31021596, PMID:37923710, PMID:35905743). Functionally, CLPP turns over respiratory chain components, TCA-cycle and metabolic enzymes, and translation machinery, cooperating with the protease LONP1 to clear substrates such as SHMT2 (PMID:26058080, PMID:33637676). Loss of CLPP destabilizes mtDNA and drives cytosolic mtDNA release that activates cGAS-STING type I interferon signaling (PMID:33731338), and produces context-dependent organismal phenotypes including impaired oocyte competence with mTOR pathway hyperactivation (PMID:29851234), a lean cold-intolerant metabolic phenotype (PMID:29588285), and altered neurodegeneration through its turnover of respiratory complex I (PMID:35240691).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 Medium

    Establishing the human CLPP gene and its conserved serine-protease active-site architecture defined the candidate as a mitochondrial protease, raising the question of how it functions.

    Evidence RACE cloning, sequence analysis, Northern blotting, and somatic cell hybrid mapping

    PMID:8543061

    Open questions at the time
    • No demonstration of proteolytic activity or partner requirement
    • Subcellular localization not yet confirmed
  2. 1998 High

    Determining that the precursor is imported into mitochondria, cleaved to a mature form, and lacks intrinsic activity established CLPP as a partner-dependent matrix protease.

    Evidence Pulse-chase, cell-free import into isolated mitochondria, immunofluorescence, and fluorogenic peptide assays

    PMID:9512494

    Open questions at the time
    • Identity of the required activating partner not established
    • Physiological substrates unknown
  3. 1999 High

    Showing the ATPase-protease complex is the functional protease that persists through many turnovers framed degradation as an ATP-stabilized partnership.

    Evidence In vitro reconstitution of E. coli ClpAP with trap variants, dissociation kinetics, and ATP-analog experiments

    PMID:10555973

    Open questions at the time
    • Bacterial system; human ClpXP not directly tested here
    • Substrate selection determinants unresolved
  4. 2010 High

    Dissecting how ClpX binding stimulates ClpP and gates substrate entry explained why isolated ClpP is restricted to small peptides.

    Evidence In vitro peptide cleavage, active-site modification, and channel-residue mutagenesis (combined with 2004 IGF-loop/sensor-II nucleotide-coupling work)

    PMID:15064753 PMID:20416323

    Open questions at the time
    • Allosteric basis of catalytic stimulation not yet structurally defined
    • Bacterial models
  5. 2011 High

    Demonstrating that ADEP antibiotics activate ClpP independent of its ATPase and drive degradation of FtsZ revealed a druggable, dysregulating activation mode.

    Evidence In vitro and in vivo ADEP treatment with microscopy and immunoblotting for FtsZ (extended in 2020 to ATPase-independent unfolding of FtsZ domains)

    PMID:21969594 PMID:32605984

    Open questions at the time
    • Bacterial ClpP; relevance to human enzyme not yet shown here
    • Full substrate scope of dysregulated ClpP undefined
  6. 2015 High

    Defining activation as allosteric conformational control of the barrel — not mere pore opening — unified chaperone- and drug-mediated stimulation around a common hydrophobic regulatory pocket.

    Evidence NMR, chemical probes, and ClpX competition binding assays

    PMID:25695750

    Open questions at the time
    • Human-specific allosteric features not yet resolved
    • Catalytic-residue conformational changes inferred
  7. 2015 Medium

    Linking human CLPP to respiratory chain and metabolic enzyme interactors and to OXPHOS maintenance established its cellular role and a cancer-relevant dependency.

    Evidence Co-IP/MS interactome and shRNA knockdown with metabolic flux analysis in AML cells, plus knockdown phenotyping in muscle cells

    PMID:26058080 PMID:26721594

    Open questions at the time
    • Direct vs. indirect substrate relationships not resolved by Co-IP
    • Single-cell-type findings
  8. 2015 Medium

    Mass-spectrometric profiling of endogenous degradation products showed barrel architecture, not strict sequence specificity, drives processing — clarifying how ClpP achieves broad substrate handling.

    Evidence Positional fluorogenic substrate libraries and MS of ClpXP degradation products, including disease-mutant ClpP

    PMID:26606371

    Open questions at the time
    • In situ specificity determinants only partially defined
    • Physiological substrate set still incomplete
  9. 2018 High

    Co-crystal structures of ADEP- and D9-bound human ClpP, and conformational-plasticity studies, identified species-selective regulatory motifs and the structural basis for dysregulating human ClpP toward apoptosis.

    Evidence X-ray co-crystallography, NMR/cryo-EM, mutagenesis, and cell viability/caspase assays

    PMID:29941580 PMID:30126533 PMID:30129683

    Open questions at the time
    • In-cell substrate spectrum of dysregulated human ClpP not yet mapped
    • Compact-vs-extended conformational preference of human enzyme unexpected
  10. 2018 Medium

    Whole-body and tissue-specific knockout mice revealed organismal roles — metabolic protection with cold intolerance and ovarian follicle maintenance via mTOR — establishing context-dependent physiology downstream of CLPP.

    Evidence Whole-body and tissue-specific Clpp knockout mice with metabolic phenotyping, ovarian histology, mTOR immunoblotting, and rapamycin rescue

    PMID:29588285 PMID:29851234

    Open questions at the time
    • Molecular substrates linking CLPP loss to mTOR activation unidentified
    • Non-cell-autonomous metabolic mechanism undefined
  11. 2019 High

    Identifying ONC201/imipridone compounds as direct human ClpP agonists, validated by knockdown, established ClpP as their on-target effector and a therapeutic activation target.

    Evidence Drug-affinity MS, recombinant ClpP peptidase assays, and siRNA knockdown of cellular responses

    PMID:31021596

    Open questions at the time
    • Cellular substrate selectivity of activated ClpP not yet profiled
    • Resistance mechanisms unaddressed
  12. 2019 High

    Mapping electrostatic-network reorganization at entrance pores and IGF-loop docking kinetics pinned down the necessary and sufficient structural events for activation and association.

    Evidence X-ray, NMR, SAXS with activating mutations, and single-chain ClpX pseudohexamer kinetic assays

    PMID:30767302 PMID:31754640

    Open questions at the time
    • Quantitative coupling between gate ordering and catalysis incomplete
    • Mostly non-human structural systems
  13. 2019 Medium

    Showing α-synuclein binds and inhibits ClpP, and that ClpP overexpression rescues α-Syn mitochondrial pathology, connected CLPP function to neurodegenerative proteostatic stress.

    Evidence Co-IP, peptidase assays, AAV ClpP overexpression in mouse brain, and iPS-derived neurons

    PMID:30877431

    Open questions at the time
    • Single Co-IP-based interaction; structural interface undefined
    • Mechanism of soluble-to-insoluble redistribution unclear
  14. 2021 Medium

    Defining LONP1/ClpP substrate cooperation and the cGAS-STING consequence of CLPP loss connected CLPP to both proteostatic clearance of metabolic enzymes and innate immune signaling.

    Evidence APEX proximity proteomics with double knockdown, and CLPP-null mice with cGAS/STING knockout and mtDNA depletion epistasis

    PMID:33637676 PMID:33731338

    Open questions at the time
    • Direct CLPP cleavage of identified substrates not all confirmed
    • Mechanism of mtDNA destabilization upon CLPP loss undefined
  15. 2022 High

    Cryo-EM of ClpP-ATPase complexes and a pH-dependent conformational switch consolidated the model of substrate translocation and equilibrium between active extended and inactive compressed states.

    Evidence Cryo-EM and NMR of ClpP and ClpP-ATPase complexes with activity correlation

    PMID:33232135 PMID:35245501

    Open questions at the time
    • Human mitochondrial ClpXP complex structure not resolved here
    • Regulation of the conformational equilibrium in vivo unclear
  16. 2022 Medium

    Showing that CLPP depletion in DARS2-deficient neurons delays neurodegeneration by reducing complex I turnover demonstrated that CLPP actively degrades respiratory complex components under translation stress.

    Evidence Cell-type-specific Dars2/Clpp double-knockout mice with OXPHOS, histology, and behavioral readouts

    PMID:35240691

    Open questions at the time
    • Complex I substrate degradation inferred, not directly captured
    • Specific CLPP-cleaved subunits unidentified
  17. 2023 High

    Co-crystal structures of imipridone- and ZK53/ZG111-class agonists with human ClpP and N-terminome profiling defined the binding chemistry and the proteomic consequences of pharmacologically dysregulated human ClpP in tumors.

    Evidence X-ray co-crystallography, N-terminome proteomics, Seahorse, and xenograft tumor models

    PMID:35905743 PMID:36586405 PMID:37923710

    Open questions at the time
    • Predictors of tumor sensitivity to ClpP agonism undefined
    • Native (non-drug) substrate cleavage rules incompletely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous, physiological substrate repertoire of human mitochondrial ClpXP and the molecular events linking CLPP loss to mtDNA instability, mTOR activation, and tissue-specific phenotypes remain to be defined.
  • No complete, directly validated native substrate set for human ClpXP
  • Mechanism connecting CLPP loss to mtDNA destabilization unknown
  • Causal substrate basis of mTOR and metabolic phenotypes unidentified

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 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
CLPXLONP1SHMT2SNCA
Complex memberships
ClpXP protease

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Human CLPP (hClpP) is a nuclear-encoded mitochondrial protein: its ~39 kDa precursor is imported into mitochondria in a membrane-potential-dependent manner, where ~56 N-terminal residues are cleaved to yield the mature ~32 kDa form. Immunofluorescence confirmed co-localization with mitochondrial Hsp60. No protease activity was detected in cell extracts without co-factors, indicating hClpP requires partners for activity. Pulse-chase/immunoprecipitation, cell-free import assay with isolated rat liver mitochondria, immunofluorescence confocal microscopy, fluorogenic peptide assays The Biochemical journal High 9512494
1995 Human CLPP gene encodes a 277-amino-acid precursor with conserved serine-protease active-site motifs and is assigned to chromosome 19. Tissue-specific expression is highest in skeletal muscle. RACE cloning, sequence analysis, Northern blotting, human/rodent somatic cell hybrid panel FEBS letters Medium 8543061
2004 ClpX-ClpP affinity is dynamically regulated: it varies with the protein-processing task of ClpX and with catalytic engagement of ClpP active sites. ATP hydrolysis by ClpX modulates the interaction via conformational changes in IGF loops that contact ClpP. A conserved arginine in the ClpX sensor II helix links nucleotide state to ClpP binding and substrate engagement. Biochemical binding assays, mutagenesis of IGF loops and sensor II helix, ATPase and proteolysis assays Nature structural & molecular biology High 15064753
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 by ClpX. Channel-loop and helix-A residues of ClpP gate substrate entry: mutations in these residues allow larger substrates into free ClpP and, in some cases, eliminate ClpX binding, supporting a model in which ClpX opens a gate that excludes larger substrates from isolated ClpP. In vitro peptide cleavage assays, active-site modification assays, site-directed mutagenesis of ClpP channel residues, ClpXP translocation assays Journal of molecular biology High 20416323
2008 N-terminal truncation of E. coli ClpP by 10–17 residues activates it for ATPase-independent, processive degradation of large unfolded substrates; removal of 14 residues is maximal. Product-size distribution is identical to ClpAP/ClpXP, indicating the ATPases do not determine product size. Residues R15 and S16 are labile and R15/I19/R24/F49 form a hydrophobic pocket maintained by the N-terminal gate. Crystal structures of ΔN14-ClpP and ΔN17-ClpP, in vitro protease assays with unfolded substrates, structural comparison Journal of structural biology High 19038348
2008 Crystal structures of Helicobacter pylori ClpP in apo form and in complex with product peptides reveal that peptide products bind across two antiparallel β-strands and point toward the adjacent active site, providing a structural basis for broad substrate specificity, product inhibition, and processive degradation within the chamber. X-ray crystallography of ClpP–peptide complex and apo structure Journal of molecular biology High 18468623
2011 ADEP antibiotics activate bacterial ClpP independent of ClpA/ClpX by switching it to an uncontrolled protease state; ADEP-activated ClpP degrades the essential cell-division protein FtsZ in vitro and in vivo, preventing Z-ring assembly and inhibiting cell division. FtsZ is particularly susceptible compared to other proteins. In vitro ClpP protease assays with ADEP, in vivo ADEP treatment with microscopy (Z-ring delocalization), immunoblotting for FtsZ Proceedings of the National Academy of Sciences of the United States of America High 21969594
2015 Both AAA+ chaperone (ClpX) and ADEP small molecules activate ClpP through allosteric conformational control of the ClpP barrel, not merely by opening the axial pore. ADEP cooperatively binds and directly stimulates catalytic residue conformation. Substoichiometric ADEP prevents ClpX binding to ClpP and partially inhibits ClpP through conformational perturbance. The hydrophobic binding pocket is identified as a major conformational regulatory site. Chemical probes, NMR, biochemical ClpP activity assays, ClpX competition binding assays Nature communications High 25695750
2018 ADEP analogs potently dysregulate human mitochondrial ClpP (HsClpP), causing non-specific substrate degradation. ADEP-HsClpP co-crystal structure reveals a highly complementary binding interface formed by two neighboring HsClpP subunits, but unexpectedly with HsClpP in the compact (not extended) conformation. ADEP-dysregulated HsClpP induces caspase-dependent intrinsic apoptosis. X-ray co-crystallography, in vitro protease activity assays, cell viability and caspase activation assays Cell chemical biology High 30126533
2018 A small molecule D9 acts as a species-selective activator of human ClpP (hClpP) by mimicking the natural chaperone ClpX. Structure-activity relationship and mutational studies reveal a unique YYW aromatic amino acid network in hClpP that tightly controls activity and substrate turnover; this motif is absent in bacterial ClpP homologs. Chemical synthesis, ClpP activity assays, site-directed mutagenesis, structural modeling, selectivity assays vs. bacterial ClpP Angewandte Chemie (International ed. in English) High 30129683
2018 Wild-type S. aureus ClpP (SaClpP) exists exclusively in an active extended conformation. A hydrophobic site mutation causes N-terminal domain unfolding, loss of activity, and formation of a novel split-ring conformation with 20-Å-wide lateral pores. ADEP binding restores the extended form and partial activity. This N-terminal conformational plasticity is conserved in E. coli and N. meningitidis ClpP. Methyl-TROSY NMR, cryo-EM, biochemical protease assays, molecular dynamics simulations, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 29941580
2019 ACP1 and ADEP small-molecule activators of ClpP induce distinct conformational changes in ClpP, but reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Formation of ordered N-terminal axial loops and reduced structural heterogeneity further enhance activation. Activating mutations recapitulate small-molecule structural effects. X-ray crystallography, methyl-TROSY NMR, small-angle X-ray scattering (SAXS), activating mutations Communications biology High 31754640
2019 IGF-motif loops of the ClpX hexameric ring mediate docking with ClpP. ATP/ATPγS binding changes ClpX ring conformation to bring IGF loops closer together, enabling multivalent contacts with ClpP docking clefts. Deletion of one or two IGF loops modestly slows ClpX-ClpP association but strongly accelerates dissociation. Loss of IGF loops reduces processivity and rate of ClpXP-mediated degradation. Single-chain ClpX pseudohexamer mutagenesis, ClpX-ClpP association/dissociation kinetic assays, ATP-dependent proteolysis assays Protein science High 30767302
2019 ONC201 and related TR imipridone compounds directly bind human mitochondrial ClpP and activate its peptidase activity in a dose- and time-dependent manner in vitro. TR compounds bind HsClpP with ~10-fold higher affinity than ONC201 and activate it ~10–100-fold more potently. siRNA knockdown of ClpP reduces cellular responses to these compounds (CHOP induction, mitochondrial protein loss, cytostasis). Immobilized drug affinity chromatography/mass spectrometry, recombinant ClpP peptidase assays, siRNA knockdown, immunoblotting ACS chemical biology High 31021596
2015 Human mitochondrial ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes as demonstrated by co-immunoprecipitation in AML cells. Knockdown of ClpP in leukemic cells inhibits oxidative phosphorylation and mitochondrial metabolism. shRNA knockdown, Co-immunoprecipitation/mass spectrometry (BioID-type interactome), Seahorse metabolic flux analysis Cancer cell Medium 26058080
2015 Knockdown of human mitochondrial ClpP (~70%) in C2C12 muscle cells reduces mitochondrial respiration (complex I and II substrates), alters mitochondrial morphology, changes expression of fission protein Drp1, blunts mitochondrial UPR induction, increases ROS, decreases membrane potential, and impairs myoblast differentiation and cell proliferation. eIF2α phosphorylation is elevated, suggesting inhibition of translation. siRNA and lentiviral shRNA knockdown, Seahorse XF assay, flow cytometry (ROS, membrane potential), immunoblotting, differentiation assays Free radical biology & medicine Medium 26721594
2015 Overexpression of human ClpP (HClpP) desensitizes cancer cells to cisplatin, while ClpP or ClpX knockdown sensitizes them. ClpP activity positively correlates with decreased cellular cisplatin accumulation and increased levels of copper efflux pumps ATP7A and ATP7B. Overexpression of catalytically inactive HClpP-S97A had no effect, establishing requirement for proteolytic activity. Overexpression and siRNA knockdown in human cancer cells, cisplatin sensitivity assays, DNA-adduct measurement, immunoblotting for ATP7A/B Biochimica et biophysica acta Medium 26675528
2019 α-Synuclein (WT and A53T mutant) physically interacts with ClpP and suppresses its peptidase activity. α-Syn binding promotes redistribution of ClpP from the soluble to the insoluble cellular fraction. ClpP deficiency induced by α-Syn overload causes mitochondrial misfolded protein accumulation, suppressed respiratory activity, and increased oxidative damage. Overexpression of ClpP rescues α-Syn-induced mitochondrial oxidative stress by increasing SOD2 levels and reduces α-Syn pathology in vivo. Co-immunoprecipitation, ClpP peptidase activity assays, viral ClpP overexpression in mouse brain (AAV), iPS-derived neurons, fractionation assays Acta neuropathologica Medium 30877431
2021 CLPP loss in mice activates type I interferon signaling via the mtDNA-cGAS-STING axis. CLPP deficiency causes mtDNA instability and altered packaging, leading to cytosolic mtDNA release. Depletion of mtDNA or cGAS-STING pathway components reduces antiviral gene expression in CLPP-null cells, placing cGAS-STING downstream of CLPP in innate immune signaling. CLPP-null mouse model, cGAS/STING genetic knockout, mtDNA depletion with ethidium bromide/dideoxycytidine, antiviral resistance assays, qPCR for IFN-stimulated genes Journal of immunology Medium 33731338
2018 CLPP-null female mice show reduced mature oocyte yield, no blastocysts, smaller mitochondria with lower aspect ratio, decreased mitochondrial fusion gene expression, increased follicular atresia, and reduced primordial follicle reserve. CLPP absence activates mTORC1 and mTORC2 signaling (elevated p-S6, p-S6K, p-4EBP1, p-AKT, p-mTOR), and rapamycin partially rescues oocyte competence, placing mTOR pathway downstream of CLPP in ovarian follicle maintenance. Clpp knockout mice, ovarian histology, oocyte and embryo phenotyping, immunoblotting for mTOR pathway components, rapamycin rescue experiment, electron microscopy of mitochondria Aging cell Medium 29851234
2018 Whole-body CLPP-deficient mice have a lean phenotype with improved glucose homeostasis and are protected from diet-induced obesity and insulin resistance. CLPP ablation impairs brown adipocyte function and adaptive thermogenesis, leaving mice unable to tolerate cold stress. Liver- or muscle-specific CLPP depletion does not recapitulate the metabolic phenotype, indicating a non-cell-autonomous mechanism. Whole-body and tissue-specific Clpp knockout mice, metabolic phenotyping (glucose tolerance, body composition), cold exposure assays, brown adipocyte functional assays EMBO reports Medium 29588285
2021 LONP1 and ClpP cooperate to maintain mitochondrial proteostasis in cancer cells. Using APEX-mediated proximity biotinylation proteomics, substrates of both proteases were identified including SHMT2, components of OXPHOS, TCA cycle, and amino acid and lipid metabolism. Simultaneous depletion of LONP1 and ClpP synergistically increases unfolded SHMT2, cancer cell death, and sensitivity to SHMT2 inhibitor. APEX-proximity proteomics, siRNA double knockdown, cell viability assays, SHMT2 inhibitor sensitivity assay Oncogenesis Medium 33637676
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. This demonstrates an ATPase-independent protein unfolding capability of ClpP when activated by a small molecule. In vitro ClpP protease assays with purified FtsZ and ADEP, nucleotide protection assays, domain-specific degradation mapping mBio High 32605984
2020 A pH-dependent conformational switch controls N. meningitidis ClpP activity: cryo-EM and NMR demonstrate an equilibrium between the active extended and inactive compressed conformations of wild-type ClpP that is regulated by pH, providing structural insight into how ClpP exploits conformational dynamics to regulate function. Cryo-EM, solution NMR spectroscopy, activity assays at different pH values Journal of the American Chemical Society High 33232135
2022 Cryo-EM structures of ClpP-ATPase complexes reveal how a hexameric ATPase and tetradecameric ClpP work together, including the mechanism of substrate unfolding and translocation and allosteric control of ClpP by ATPases. Small molecules and gain/loss-of-function mutations provide additional insights into ClpP conformational regulation. Cryo-EM structural determination of ClpP-ATPase complexes, structure-function analysis with mutants and small molecules The Journal of biological chemistry Medium 35245501
2022 CLPP depletion in DARS2-deficient neurons (Purkinje cells, cortical/hippocampal neurons) delays neurodegeneration in vivo, reduces OXPHOS dysfunction, decreases neuroinflammation, and improves motor function. This is proposed to result from diminished turnover of respiratory complex I by CLPP, suggesting CLPP actively degrades complex I components under conditions of mitochondrial translation deficiency. Cell-type-specific Dars2/Clpp double knockout mice, histology, OXPHOS activity assays, behavioral testing, neuroinflammation markers Brain Medium 35240691
2022 X-ray co-crystal structures of imipridone-derived ClpP agonists bound to human ClpP reveal enhanced binding affinity due to improved shape and charge complementarity with surface hydrophobic pockets. N-terminome profiling of cancer cells identified the structural motifs preferred for cleavage by compound-activated ClpP and global proteomic changes caused by dysregulated ClpP activity. X-ray crystallography, biochemical binding assays, N-terminome proteomics in cancer cells Structure High 36586405
2023 Crystal structure of the ZK53/human ClpP complex reveals π-π stacking essential for selective ligand binding to the mitochondrial ClpP hydrophobic pocket. ZK53 activates ClpP to degrade electron transport chain components in a ClpP-dependent manner, reducing OXPHOS and ATP production, activating ATF-mediated DNA damage response, and triggering cell cycle arrest in lung squamous cell carcinoma. X-ray co-crystallography, biochemical ClpP activity assays, seahorse XF, immunoblotting, xenograft mouse models Nature communications High 37923710
2015 ClpP barrel architecture attenuates cleavage specificity: while recombinant ClpP from E. coli, S. aureus, and human mitochondria show preferences at P1/P2/P3 positions with fluorogenic substrates, mass spectrometric analysis of endogenous ClpXP-degradation products shows this specificity is not retained in situ. The barrel architecture concentrates substrates to enable efficient processing despite attenuated primary-sequence specificity. Fluorogenic substrate library (positional scanning), mass spectrometry of ClpXP degradation products, activity assays with cancer/Perrault-syndrome ClpP mutants ACS chemical biology Medium 26606371
2022 ZG111, a potent ClpP activator, binds directly to human ClpP and promotes ClpP-mediated degradation of respiratory chain complexes. This activates JNK/c-Jun pathway and induces ER stress response, causing growth arrest of pancreatic ductal adenocarcinoma (PDAC) cells. Biochemical ClpP binding and activity assays, immunoblotting for respiratory complexes and JNK/c-Jun pathway, PDAC xenograft and patient-derived xenograft mouse models Cell chemical biology Medium 35905743
1999 E. coli ClpA and ClpP remain associated during multiple rounds of substrate degradation (ClpAP complex stability: t1/2 ~7.5 min; casein k_cat ~10 min-1, so tens of substrate turnovers occur per complex before dissociation). ATP binding stabilizes the ClpA hexamer and ClpAP complex; mutations in the N-terminal ATP binding site accelerate dissociation. The ClpAP complex is the functional form of the protease. In vitro protease reconstitution, trap experiments using inactive ClpA/ClpP variants, dissociation kinetics, ATPase activity assays, ATP analog experiments Biochemistry High 10555973

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer cell 294 26058080
2003 Alternative roles of ClpX and ClpP in Staphylococcus aureus stress tolerance and virulence. Molecular microbiology 266 12791139
2007 Clp ATPases and ClpP proteolytic complexes regulate vital biological processes in low GC, Gram-positive bacteria. Molecular microbiology 236 17302811
2007 ClpP: a distinctive family of cylindrical energy-dependent serine proteases. FEBS letters 189 17499722
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 180 16885446
2019 Mitochondrial Protease ClpP is a Target for the Anticancer Compounds ONC201 and Related Analogues. ACS chemical biology 162 31021596
1998 Stress induction of the Bacillus subtilis clpP gene encoding a homologue of the proteolytic component of the Clp protease and the involvement of ClpP and ClpX in stress tolerance. Molecular microbiology 160 9643546
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 148 21969594
1995 The stroma of higher plant plastids contain ClpP and ClpC, functional homologs of Escherichia coli ClpP and ClpA: an archetypal two-component ATP-dependent protease. The Plant cell 144 7580259
2004 Communication between ClpX and ClpP during substrate processing and degradation. Nature structural & molecular biology 126 15064753
2018 The Role of ClpP Protease in Bacterial Pathogenesis and Human Diseases. ACS chemical biology 122 29775273
2002 Global transcriptional analysis of clpP mutations of type 2 Streptococcus pneumoniae and their effects on physiology and virulence. Journal of bacteriology 121 12057945
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 112 33037181
2015 AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control. Nature communications 109 25695750
2002 Regulation and Physiological Significance of ClpC and ClpP in Streptococcus mutans. Journal of bacteriology 109 12399506
2012 ClpP: a structurally dynamic protease regulated by AAA+ proteins. Journal of structural biology 101 22595189
2013 Trapping and proteomic identification of cellular substrates of the ClpP protease in Staphylococcus aureus. Journal of proteome research 99 23253041
2018 Acyldepsipeptide Analogs Dysregulate Human Mitochondrial ClpP Protease Activity and Cause Apoptotic Cell Death. Cell chemical biology 95 30126533
2018 Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre-implantation embryos. Aging cell 90 29851234
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
2019 Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity. Acta neuropathologica 73 30877431
2007 Role of ClpP in biofilm formation and virulence of Staphylococcus epidermidis. Microbes and infection 72 17890122
2008 Frataxin deficiency causes upregulation of mitochondrial Lon and ClpP proteases and severe loss of mitochondrial Fe-S proteins. The FEBS journal 70 19154341
2008 Decreased expression of the mitochondrial matrix proteases Lon and ClpP in cells from a patient with hereditary spastic paraplegia (SPG13). Neuroscience 68 18378094
2010 Control of substrate gating and translocation into ClpP by channel residues and ClpX binding. Journal of molecular biology 67 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
2002 The clpP multigene family for the ATP-dependent Clp protease in the cyanobacterium Synechococcus. Microbiology (Reading, England) 62 12101312
2022 Recent structural insights into the mechanism of ClpP protease regulation by AAA+ chaperones and small molecules. The Journal of biological chemistry 60 35245501
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 58 22112206
2004 The ClpP peptidase is the major determinant of bulk protein turnover in Bacillus subtilis. Journal of bacteriology 57 15317791
2021 LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival. Oncogenesis 56 33637676
1998 A human homologue of Escherichia coli ClpP caseinolytic protease: recombinant expression, intracellular processing and subcellular localization. The Biochemical journal 56 9512494
2018 Selective Activation of Human Caseinolytic Protease P (ClpP). Angewandte Chemie (International ed. in English) 54 30129683
2009 ClpP of Streptococcus mutans differentially regulates expression of genomic islands, mutacin production, and antibiotic tolerance. Journal of bacteriology 52 20038588
2022 Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma. Cell chemical biology 51 35905743
2018 CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis. EMBO reports 51 29588285
1999 ClpA and ClpP remain associated during multiple rounds of ATP-dependent protein degradation by ClpAP protease. Biochemistry 51 10555973
2019 Chemical Modulation of Human Mitochondrial ClpP: Potential Application in Cancer Therapeutics. ACS chemical biology 49 31241890
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
2021 Substrates and interactors of the ClpP protease in the mitochondria. Current opinion in chemical biology 48 34446368
2013 The ClpP protease is required for the stress tolerance and biofilm formation in Actinobacillus pleuropneumoniae. PloS one 48 23326465
1995 Human ClpP protease: cDNA sequence, tissue-specific expression and chromosomal assignment of the gene. FEBS letters 48 8543061
2021 Human ClpP protease, a promising therapy target for diseases of mitochondrial dysfunction. Drug discovery today 45 33460621
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
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 45 28555174
2016 The development of small-molecule modulators for ClpP protease activity. Molecular bioSystems 45 27831584
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
2002 Distinct clpP genes control specific adaptive responses in Bacillus thuringiensis. Journal of bacteriology 42 12270812
2023 Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma. Nature communications 41 37923710
2020 ClpP regulates breast cancer cell proliferation, invasion and apoptosis by modulating the Src/PI3K/Akt signaling pathway. PeerJ 41 32195060
2003 Heat and DNA damage induction of the LexA-like regulator HdiR from Lactococcus lactis is mediated by RecA and ClpP. Molecular microbiology 41 14617183
2022 Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome. Structure (London, England : 1993) 40 36586405
2011 Cloning and expression of protease ClpP from Streptococcus pneumoniae in Escherichia coli: study of the influence of kanamycin and IPTG concentration on cell growth, recombinant protein production and plasmid stability. Vaccine 40 21651937
2022 ClpP inhibitors are produced by a widespread family of bacterial gene clusters. Nature microbiology 39 35246663
2006 Construction and characterization of a Lactococcus lactis strain deficient in intracellular ClpP and extracellular HtrA proteases. Microbiology (Reading, England) 39 16946256
2022 Quercetin Reduces the Virulence of S. aureus by Targeting ClpP to Protect Mice from MRSA-Induced Lethal Pneumonia. Microbiology spectrum 38 35319277
2022 Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP. Pharmacology research & perspectives 38 35929764
2008 Polar localization and compartmentalization of ClpP proteases during growth and sporulation in Bacillus subtilis. Journal of bacteriology 38 18689476
2008 Turned on for degradation: ATPase-independent degradation by ClpP. Journal of structural biology 37 19038348
2022 Cellular functions of the ClpP protease impacting bacterial virulence. Frontiers in molecular biosciences 36 36533084
2005 The ClgR protein regulates transcription of the clpP operon in Bifidobacterium breve UCC 2003. Journal of bacteriology 36 16321946
2019 ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores. Communications biology 35 31754640
2017 The Protein Chaperone ClpX Targets Native and Non-native Aggregated Substrates for Remodeling, Disassembly, and Degradation with ClpP. Frontiers in molecular biosciences 35 28523271
2015 Barrel-shaped ClpP Proteases Display Attenuated Cleavage Specificities. ACS chemical biology 35 26606371
2020 ClpP participates in stress tolerance, biofilm formation, antimicrobial tolerance, and virulence of Enterococcus faecalis. BMC microbiology 34 32033530
2022 Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice. Journal of hepatology 32 35421426
2015 Mitochondrial ClpP activity is required for cisplatin resistance in human cells. Biochimica et biophysica acta 32 26675528
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 30 32605984
2019 Roles of the ClpX IGF loops in ClpP association, dissociation, and protein degradation. Protein science : a publication of the Protein Society 30 30767302
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 30 31399403
2016 Effect of clpP and clpC deletion on persister cell number in Staphylococcus aureus. Journal of medical microbiology 29 27375177
2019 Role of ClpX and ClpP in Streptococcus suis serotype 2 stress tolerance and virulence. Microbiological research 28 31178057
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
2020 Global Inventory of ClpP- and ClpX-Regulated Proteins in Staphylococcus aureus. Journal of proteome research 27 33210542
2020 Development of Antibiotics That Dysregulate the Neisserial ClpP Protease. ACS infectious diseases 27 33237740
2024 A review of current therapeutics targeting the mitochondrial protease ClpP in diffuse midline glioma, H3 K27-altered. Neuro-oncology 26 37589388
2017 From discovery of the CHOP axis and targeting ClpP to the identification of additional axes of the UPRmt driven by the estrogen receptor and SIRT3. Journal of bioenergetics and biomembranes 26 28799020
2022 Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis. Cancer research communications 25 36388465
2018 Initial Characterization of the Two ClpP Paralogs of Chlamydia trachomatis Suggests Unique Functionality for Each. Journal of bacteriology 25 30396899
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
2020 Structural determinants of regulated proteolysis in pathogenic bacteria by ClpP and the proteasome. Current opinion in structural biology 23 33221704
2017 A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents. Bioorganic & medicinal chemistry 22 28917450
2009 A moss pentatricopeptide repeat protein binds to the 3' end of plastid clpP pre-mRNA and assists with mRNA maturation. The FEBS journal 22 19740105
2017 An amino acid domino effect orchestrates ClpP's conformational states. Current opinion in chemical biology 20 28910721
2017 Activation of a Cell Surface Signaling Pathway in Pseudomonas aeruginosa Requires ClpP Protease and New Sigma Factor Synthesis. Frontiers in microbiology 20 29312164
2019 Mitochondrial unfolded protein response gene CLPP changes mitochondrial dynamics and affects mitochondrial function. PeerJ 19 31304066
2022 Nepetin reduces virulence factors expression by targeting ClpP against MRSA-induced pneumonia infection. Virulence 18 35363605
2003 The plastid clpP gene may not be essential for plant cell viability. Plant & cell physiology 18 12552152
2023 Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer. Frontiers in pharmacology 17 37063293
2022 CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis. Brain : a journal of neurology 17 35240691
2020 Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease. Neurogenetics 17 32342250
2023 ClpP protease modulates bacterial growth, stress response, and bacterial virulence in Brucella abortus. Veterinary research 16 37612737
2020 Dioctatin Activates ClpP to Degrade Mitochondrial Components and Inhibits Aflatoxin Production. Cell chemical biology 16 32888498
2020 A pH-Dependent Conformational Switch Controls N. meningitidis ClpP Protease Function. Journal of the American Chemical Society 16 33232135

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