CLPP is the serine-protease subunit of mitochondrial ClpXP. After import into the matrix, mature CLPP subunits assemble proteolytic rings whose active sites face an enclosed chamber. CLPX docks to CLPP and uses ATP to recognize, unfold and translocate protein substrates; CLPP cleaves the delivered polypeptides. Oligomeric stability and activity depend on the preparation and activation state. This division of labor supports mitochondrial protein turnover and quality control. Mouse studies implicate ClpXP in ERAL1 turnover during mitoribosome maturation and in renewal of respiratory complex I N-module proteins. Human biochemical experiments establish CLPP catalysis, CLPX coupling and activation by imipridone compounds. Phosphoserine-dependent substrate recognition is supplied by CLPX. Biallelic CLPP variants cause Perrault syndrome, with sensorineural hearing loss and ovarian dysfunction; tested variants affect catalytic activity, oligomerization or CLPX coupling differently. CLPP-dependent mitochondrial stress signaling varies by model: the worm ortholog contributes to the mitochondrial unfolded-protein response, whereas the tested mouse Dars2-deficient cardiac and human SPG7-depletion systems can mount the assayed response without CLPP.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004175 endopeptidase activity | IDA PMID:22354088 Mitochondrial processing peptidase regulates PINK1 processin... | ACCEPT | Summary: Human CLPP directly cleaves internal peptide bonds. Reason: The cited PINK1 RNAi study implicates CLPP but also reports impaired respiration and cell viability after CLPP depletion; reconstituted human ClpXP and active-site mutants independently establish the enzyme activity. This acceptance does not identify a direct PINK1 cleavage site. |
| GO:0004176 ATP-dependent peptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Human CLPP supplies peptide-bond hydrolysis in the ATP-dependent ClpXP protease, while CLPX supplies ATP hydrolysis and substrate translocation. Reason: Current bacterial source annotations and direct human reconstitution support the inherited activity at this coupled-complex scope. The historical PAINT tree and ancestral placement were not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000043558 UNRESOLVED Historical PAINT node placement and alignment were not inspected. The separately listed experimental source records corroborate the target function, but do not resolve this ancestral entity. UniProtKB:P0A6G7 SUPPORTS TRANSFER Current experimental records for GO:0004176 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. UniProtKB:P80244 SUPPORTS TRANSFER Current experimental records for GO:0004176 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. |
| GO:0004176 ATP-dependent peptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro ClpP-family assignment agrees with direct human reconstitution of an ATP-dependent protease. Reason: ATP dependence describes CLPP functioning with CLPX; it does not assign ATP hydrolysis to CLPP. |
| GO:0004176 ATP-dependent peptidase activity | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Reactome models ATP-consuming degradation by a CLPXP complex containing human CLPP and CLPX in the mitochondrial matrix. Reason: CLPP supplies the proteolytic component of this coupled activity. The black-box reaction does not separate ATP consumption by CLPX from peptide cleavage by CLPP. |
| GO:0004252 serine-type endopeptidase activity | EXP PMID:15522782 Crystallography and mutagenesis point to an essential role f... | ACCEPT | Summary: Human CLPP is a serine endopeptidase. Reason: The original crystallography and mutagenesis study identifies the mature-protein Ser97/His122/Asp171 catalytic triad and tests the role of the axial pore in proteolysis. Its mature-protein numbering differs from precursor numbering in UniProt. Supporting Evidence: file:human/CLPP/CLPP-uniprot.txt Abolishes protease activity. |
| GO:0004252 serine-type endopeptidase activity | EXP PMID:22354088 Mitochondrial processing peptidase regulates PINK1 processin... | ACCEPT | Summary: The original PINK1 study detects a CLPP-dependent processing phenotype, with respiratory and viability confounding explicitly acknowledged. Reason: Serine-dependent catalysis is independently established by human CLPP reconstitution and active-site mutagenesis; the PINK1 phenotype alone does not identify CLPP substrate recognition or a cleavage site. |
| GO:0004252 serine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Human CLPP catalytic mutagenesis and reconstitution directly support the serine-endopeptidase activity. Reason: Target self-inclusion among the PAINT sources is legitimate experimental grounding. Current bacterial and fly source records corroborate the family activity; the historical node/alignment and unresolved WormBase identifier mapping were not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0032229 SUPPORTS TRANSFER Current experimental records for GO:0004252 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. PANTHER:PTN000043558 UNRESOLVED Historical PAINT node placement and alignment were not inspected. The separately listed experimental source records corroborate the target function, but do not resolve this ancestral entity. UniProtKB:P80244 SUPPORTS TRANSFER Current experimental records for GO:0004252 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. UniProtKB:Q16740 SUPPORTS TRANSFER Current experimental records for GO:0004252 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. WB:WBGene00014172 UNRESOLVED The exact current source mapping or historical evidence remains unresolved; no negative biological conclusion is inferred from the lookup limit. |
| GO:0004252 serine-type endopeptidase activity | IDA PMID:11923310 Functional proteolytic complexes of the human mitochondrial ... | ACCEPT | Summary: Recombinant human CLPP with CLPX degrades protein substrates, and active-site S97A/C variants in the paper's mature-protein numbering lose proteolysis. Reason: Substrate trapping was demonstrated specifically for S97A. Human/bacterial component swaps assign substrate choice to ClpX rather than CLPP. |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined InterPro and EC mapping agrees with human CLPP active-site chemistry and proteolysis. Reason: The ATP-dependent enzyme classification describes the coupled protease; the serine nucleophile and peptide cleavage belong to CLPP. Supporting Evidence: GO_REF:0000120 file:human/CLPP/CLPP-uniprot.txt EC=3.4.21.92 |
| GO:0005515 protein binding | IPI PMID:11923310 Functional proteolytic complexes of the human mitochondrial ... | MODIFY | Summary: Human CLPP physically associates with the AAA+ ATPase CLPX in reconstituted proteolytic complexes. Reason: ATPase binding is the informative partner class and is integrated into the protease core. Proposed replacements: ATPase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16115876 Human mitochondrial ClpP is a stable heptamer that assembles... | MODIFY | Summary: The complete accessible abstract directly reports ATP-dependent association of human CLPX with CLPP and stimulation of proteolytic activity. Reason: The accessible original abstract directly reports association and an active human ClpXP complex in ATP-containing conditions. This supports ATPase binding without assigning ATP hydrolysis to CLPP; the full article remains unavailable. Proposed replacements: ATPase binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Positive source-specific binding to EFEMP2. Reason: The validated human Y2H pair identifies EFEMP2 / fibulin-4 (O95967), an authenticated extracellular-matrix component. GO:0050840 explicitly covers binding an ECM component, so the specific class fits this tested interaction without requiring an assembled matrix or establishing extracellular CLPP localization, matrix remodeling, or a native extracellular mechanism. Proposed replacements: extracellular matrix binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive source-specific binding to PSMB1. Reason: The exact validated Y2H records support binding to the non-catalytic proteasome beta subunit PSMB1. A subunit pair does not demonstrate binding to an assembled proteasome or to a catalytically active protease. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Positive source-specific binding to GRN. Reason: Validated Y2H records identify P28799 progranulin, whose reviewed human record includes experimentally supported growth-factor function. The growth-factor-binding definition concerns the bound protein class; it does not require CLPP to stimulate proliferation. The assay does not resolve a processed granulin peptide or establish physiological encounter between matrix-localized CLPP and secreted progranulin. Proposed replacements: growth factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive source-specific binding to NUTF2. Reason: The exact validated Y2H records support binding to nuclear transport factor 2. Nuclear transport through a pore does not by itself make this partner a transmembrane transporter. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Positive source-specific binding to PPP2CA. Reason: The validated pair identifies P67775, the catalytic alpha protein of PP2A. GO:0051721 is an enzyme/phosphatase-binding term and does not require binding an assembled PP2A holoenzyme. Retain this measured catalytic-protein association without claiming a holoenzyme interaction, phosphatase regulation, or a native CLPP dephosphorylation pathway. Proposed replacements: protein phosphatase 2A binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Positive source-specific binding to EFEMP1. Reason: The validated human Y2H pair identifies EFEMP1 / fibulin-3 (Q12805), an authenticated extracellular-matrix component. GO:0050840 explicitly covers binding an ECM component, so the specific class fits this tested interaction without requiring an assembled matrix or establishing extracellular CLPP localization, matrix remodeling, or a native extracellular mechanism. Proposed replacements: extracellular matrix binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive source-specific binding to P4HA3. Reason: The exact validated Y2H records support the pair with the collagen prolyl hydroxylase alpha subunit. The record is retained as a secondary interaction; no CLPP role in collagen hydroxylation follows from it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Positive source-specific binding to DTX2. Reason: The validated pair identifies Q86UW9 DTX2, whose reviewed functional record directly supports E3 ubiquitin-ligase activity. GO:0031625 therefore describes the bound enzyme class. The Y2H result does not demonstrate that CLPP is ubiquitinated by DTX2 or that the proteins operate together in mitochondria. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Positive source-specific binding to RBPMS isoform C. Reason: The exact Q93062-3 record identifies RBPMS isoform C, the product assigned Smad coactivation in the reviewed UniProt record. PMID:17099224 directly demonstrates Smad association and enhanced tethered-Smad reporter activity; it also retains a possible post-transcriptional contribution. This supports the coactivator-binding class at the tested-pair scope, without assigning CLPP transcriptional regulation or proving native colocalization. Proposed replacements: transcription coactivator binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Positive source-specific binding to PLSCR4. Reason: The exact Q9NRQ2 pair is supported by validated Y2H. The partner class is not inferred from its name alone: PMID:23089641 reports recombinant human PLSCR4 functional reconstitution, metal-dependent phospholipid scrambling and reduced activity of Asp290Ala. This supports binding a transmembrane phospholipid transporter while leaving native CLPP encounter and any regulation of scrambling unestablished; only the complete original abstract was accessible for this biochemical paper. Proposed replacements: transmembrane transporter binding Supporting Evidence: PMID:23089641 mediate scrambling activity independent of the phospholipid head group |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive source-specific binding to C14orf119. Reason: The exact validated Y2H records support this pair. The available partner identity does not resolve a more informative binding class; the positive result is retained outside the protease core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive source-specific binding to ABI2 isoform 2. Reason: The exact Q9NYB9-2 Y2H pair remains positive. ABI2 is a WAVE/SCAR actin-regulatory-complex component, but the strongest reviewed cytoskeletal localization observations specify isoform 1. Retention of tSNARE and SH3 sequences in isoform 2 does not by itself establish that this tested product is a protein component of the cytoskeleton as required by GO:0008092. Keep the measured interaction without that unresolved class refinement; this is not evidence that ABI2-2 cannot participate in cytoskeletal regulation. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Positive source-specific binding to TNPO3. Reason: The exact validated Y2H records support the pair with transportin-3, a beta-importin family nuclear transport receptor. This is not evidence for alpha-importin binding or transmembrane-solute-transporter binding. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Positive source-specific binding to WFS1. Reason: The neurodegenerative-disease interaction screen supports the exact WFS1 pair. Wolframin has regulatory roles in membrane physiology; these records do not establish that CLPP binds a defined ion channel or participates in that regulation. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Positive source-specific binding to APP. Reason: The exact screen records include APP mutation features at residues 670–671. The tested interaction is retained with those construct limits; it is not generalized to native APP processing or CLPP-mediated amyloid production. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Positive source-specific binding to SNCA. Reason: The exact screen records carry SNCA mutation features at positions 30 and 46. They support the tested pair, without demonstrating that CLPP is a chaperone or participates in a native synuclein folding pathway. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Positive source-specific binding to HTT. Reason: The exact screen records use huntingtin fragments spanning 1–88 or 1–511 with recorded mutation features. Their positive binding is retained without extension to full-length native huntingtin or its cellular activities. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Summary: Positive source-specific binding to DNM2 isoform 2. Reason: The exact P50570-2 records support binding to dynamin-2, a GTPase rather than a small GTPase. The official four-residue splice deletion leaves its G domain intact, so GTPase binding is supported at the tested-pair scope. Proposed replacements: GTPase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Summary: Positive source-specific binding to ATXN3. Reason: The exact screen records support the ataxin-3 pair with recorded construct features. Ataxin-3 is a Josephin-family deubiquitinating protease, making protease binding the informative partner class; no deubiquitination activity is assigned to CLPP. Proposed replacements: protease binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Positive source-specific binding to TARDBP. Reason: The exact screen records include TARDBP mutation features and their recorded interaction effects. They support the tested pair, without establishing a transcription-factor-binding class or RNA-related activity for CLPP. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Positive source-specific binding to GDAP1. Reason: The exact screen records test the GDAP1 fragment spanning residues 69–358. The GST-like fold does not establish a glutathione-transferase activity for this partner, and the positive interaction is retained without that inference. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Positive source-specific binding to JPH3. Reason: The exact screen records support the junctophilin-3 pair. Its membrane-junction role does not by itself identify a narrower binding class or a physiological junctional role for CLPP. Supporting Evidence: |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The MitoCoP study provides the original high-throughput mitochondrial annotation. Reason: Its multidimensional human-cell proteomics methods were inspected, but the specific supplementary CLPP row was not recovered. Independent human immunolocalization establishes the same broad location, so the positive curated HTP assertion is retained without pretending that its target table was inspected. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: The source is HPA immunofluorescence curation. Reason: The actual human CLPP XML record reports supported mitochondrial staining in A-431, U-251MG and U2OS cells. Its separate mouse NIH3T3 annotation is not substituted for the human localization. |
| GO:0005739 mitochondrion | IDA PMID:22354088 Mitochondrial processing peptidase regulates PINK1 processin... | ACCEPT | Summary: The original PINK1 work studies CLPP within mitochondria; it is not a clean new localization assay for every protease in the screen. Reason: Independent human immunofluorescence and immunoelectron microscopy support mitochondrial localization, preserving the positive source assertion. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: The current mouse Clpp record contains experimentally supported mitochondrial localization, corroborated independently by direct human localization. Reason: The historical Ensembl transfer path was not reconstructed; the exact original donor and protein identifiers remain intact. |
| GO:0005759 mitochondrial matrix | EXP PMID:22354088 Mitochondrial processing peptidase regulates PINK1 processin... | ACCEPT | Summary: CLPP is the matrix protease component considered in the PINK1 processing study. Reason: Human matrix localization is independently supported by immunoelectron microscopy; detailed MPP-specific protease-protection experiments are not transferred to CLPP. |
| GO:0005759 mitochondrial matrix | IDA PMID:10525407 Mitochondrial localization and oligomeric structure of HClpP... | ACCEPT | Summary: The complete accessible abstract reports antibody-based immunofluorescence and immunoelectron microscopy placing mammalian CLPP in the mitochondrial matrix, including human and rat preparations. Reason: The full original localization figures were not inspected. Supporting Evidence: |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt mitochondrial-matrix vocabulary mapping agrees with directly measured human CLPP localization. Reason: This is a valid location mapping rather than evidence for a new membrane-bound catalytic activity. |
| GO:0005759 mitochondrial matrix | NAS PMID:15522782 Crystallography and mutagenesis point to an essential role f... | ACCEPT | Summary: The crystallography paper describes human CLPP as a mitochondrial matrix enzyme; this inherited NAS is retained at that statement scope. Reason: The paper's recombinant structure is not relabeled as a localization experiment. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: The binding event contains a matrix CLPXP complex whose CLPP physical entity resolves to Q16740. Reason: This directly supports the modeled location; substrate binding by the whole complex is not assigned wholesale to CLPP. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: The degradation reaction uses the same matrix CLPXP catalyst with an explicitly identified Q16740 component. Reason: The compartment assignment supports mitochondrial-matrix localization independently of uncertainties in the black-box substrate model. |
| GO:0006508 proteolysis | IDA PMID:15522782 Crystallography and mutagenesis point to an essential role f... | ACCEPT | Summary: Human CLPP substrate-cleavage and pore-mutagenesis experiments establish performed proteolysis. Reason: CLPP supplies the bond-cleaving chemistry, while its CLPX partner supplies substrate unfolding and ATP-dependent delivery. |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | Summary: The ClpP family mapping is supported by the directly demonstrated peptide-bond cleavage of human CLPP. Reason: This is performed proteolysis, rather than a process inferred solely from a loss-of-function phenotype. |
| GO:0006515 protein quality control | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited quality-control annotation agrees with CLPP's performed proteolysis of mitochondrial proteins. Reason: Human reconstitution and model-system turnover studies support the function; current donor records are corroboration, not a reconstruction of the historical PAINT node. No separate mitoribosome-assembly or stress-signaling process is added. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0032229 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. PANTHER:PTN000043558 UNRESOLVED Historical PAINT node placement and alignment were not inspected. The separately listed experimental source records corroborate the target function, but do not resolve this ancestral entity. UniProtKB:P0A6G7 SUPPORTS TRANSFER Current experimental records for GO:0006515 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. |
| GO:0008233 peptidase activity | TAS PMID:8543061 Human ClpP protease: cDNA sequence, tissue-specific expressi... | MODIFY | Summary: The cloning paper identifies conserved ClpP catalytic motifs and provides the original broad peptidase assertion. Reason: Subsequent direct human active-site and cleavage experiments support refinement to serine-type endopeptidase activity; the cloning abstract is not represented as a catalytic assay. Proposed replacements: serine-type endopeptidase activity |
| GO:0009368 endopeptidase Clp complex | IBA GO_REF:0000033 | ACCEPT | Summary: Human CLPP is demonstrably part of a Clp protease complex. Reason: The broad inherited complex term is retained across the bacterial, plastid and mitochondrial sources; their current identities and records were checked where resolvable, but the ancestral node was not reconstructed. Target self-inclusion reflects genuine human experimental grounding. The directly supported human mitochondrial specialization is represented in the source-specific experimental refinements. Propagation Review Root cause: NO FAILURE CORE Sources checked: AGI_LocusCode:AT1G02560 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. AGI_LocusCode:AT1G11750 UNRESOLVED The exact current source mapping or historical evidence remains unresolved; no negative biological conclusion is inferred from the lookup limit. AGI_LocusCode:AT1G12410 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. AGI_LocusCode:AT1G49970 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. AGI_LocusCode:AT1G66670 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. AGI_LocusCode:AT5G23140 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. AGI_LocusCode:AT5G45390 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. FB:FBgn0032229 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. PANTHER:PTN000043558 UNRESOLVED Historical PAINT node placement and alignment were not inspected. The separately listed experimental source records corroborate the target function, but do not resolve this ancestral entity. UniProtKB:P0A6G7 SUPPORTS TRANSFER Current experimental records for GO:0009368 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. UniProtKB:P56772 UNRESOLVED The current identity is resolved, but the inspected same-term records are propagated or nonexperimental; the historical experimental basis was not independently reconstructed. This is an access/provenance limit, not evidence against the target function. UniProtKB:Q16740 SUPPORTS TRANSFER Current experimental records for GO:0009368 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. |
| GO:0009368 endopeptidase Clp complex | IDA PMID:11923310 Functional proteolytic complexes of the human mitochondrial ... | MODIFY | Summary: Reconstituted human CLPX and CLPP form the mitochondrial Clp protease. Reason: The mitochondrial complex term is more informative for this human experimental assertion while preserving the original broad source identity. Proposed replacements: mitochondrial endopeptidase Clp complex Supporting Evidence: |
| GO:0009368 endopeptidase Clp complex | IPI PMID:15522782 Crystallography and mutagenesis point to an essential role f... | MODIFY | Summary: Human CLPP assembles a compartmentalized proteolytic ring complex and interacts functionally with CLPX. Reason: The human mitochondrial endopeptidase Clp complex is the appropriate specific complex class; oligomeric state depends on preparation and activation conditions. Proposed replacements: mitochondrial endopeptidase Clp complex Supporting Evidence: PMID:15522782 aqueous chamber formed by face-to-face assembly file:human/CLPP/CLPP-uniprot.txt Fourteen CLPP subunits assemble into 2 heptameric rings |
| GO:0030163 protein catabolic process | IDA PMID:11923310 Functional proteolytic complexes of the human mitochondrial ... | ACCEPT | Summary: Reconstituted human ClpXP degrades protein substrates, and loss of CLPP catalytic activity blocks cleavage. Reason: CLPP therefore performs a step of protein catabolism; this assertion does not rely solely on a knockout requirement. Supporting Evidence: |
| GO:0033619 membrane protein proteolysis | IDA PMID:22354088 Mitochondrial processing peptidase regulates PINK1 processin... | KEEP AS NON CORE | Summary: The actual PINK1 screen found CLPP depletion altered PINK1 processing, but CLPP depletion also impaired respiration and cell survival, limiting interpretation. Reason: The authors did not observe CLPP-dependent Parkin recruitment, and MPP-specific rescue and import-protection results do not establish an equivalent CLPP mechanism. Retain the source-specific membrane-protein processing association outside the core without asserting direct PINK1 cleavage. Supporting Evidence: PMID:22354088 implicate three more proteases, MPP, m-AAA and ClpXP |
| GO:0035694 mitochondrial protein catabolic process | TAS Reactome:R-HSA-9837999 | ACCEPT | Summary: The pathway includes CLPXP-mediated degradation of mitochondrial matrix proteins, with human CLPP explicitly identified as a proteolytic subunit. Reason: Direct human reconstitution supports performed protein catabolism. The pathway's broader stress-response narrative is not itself evidence for a human UPRmt signaling annotation. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CLPP self-association is supported independently by human oligomeric structures and biochemical assembly. Reason: The current rat record carries an interaction assertion, but its exact historical Ensembl propagation was not reconstructed. Retain the original identical-protein binding as assembly context; it does not specifically demonstrate a dimer or warrant a separate core. Supporting Evidence: GO_REF:0000107 PMID:16115876 isolated human mitochondrial ClpP (hClpP) is stable as a heptamer |
| GO:0051117 ATPase binding | IBA GO_REF:0000033 | ACCEPT | Summary: Direct human CLPX–CLPP association supports ATPase binding, consistent with current bacterial source records. Reason: This interaction is integrated into the protease mechanism. The historical PAINT placement was not inspected, and binding to an ATPase does not make CLPP an ATPase. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000043558 UNRESOLVED Historical PAINT node placement and alignment were not inspected. The separately listed experimental source records corroborate the target function, but do not resolve this ancestral entity. UniProtKB:P0A6G7 SUPPORTS TRANSFER Current experimental records for GO:0051117 are retained with their exact evidence and references in the source index; these support the donor premise without reconstructing the historical PAINT tree. |
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Download this section (compressed HTML)Q: How should the existing enables ATP-dependent peptidase assertion for CLPP be represented alongside the experimentally separable ATPase and substrate-translocation activities of CLPX?
Q: Which CLPP screen interactions occur in native cellular compartments, and which depend on the recorded isoforms, mutations or fragments?
Q: How do residual catalytic activity, assembly and human CLPX coupling differ among patient CLPP alleles in their native mitochondrial context?
Q: Which stress conditions require human CLPP for UPRmt signaling beyond the specific mouse cardiac and human SPG7-depletion models already tested?
Experiment: Compare imported patient variants with wild-type CLPP in matched human cells, measuring maturation, oligomeric state, CLPX association and substrate turnover. Include catalytically inactive and expression-matched controls so assembly defects are distinguished from loss of proteolysis.
Hypothesis: Patient alleles with distinct defects in isolated assays differ in residual proteolysis and CLPX coupling after mitochondrial import.
Experiment: Select representative retained screen pairs and compare the exact screened constructs with their native full-length counterparts using orthogonal interaction assays and compartment controls. Test direct binding separately from colocalization or proximity.
Hypothesis: Some positive screen pairs depend on the assayed fragment or mutation rather than the native full-length partner.
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