{"gene":"CCT5","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2006,"finding":"A missense mutation H147R in CCT5 (exon 4, A492G) causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia in humans, identifying CCT5 as the first human CCT subunit gene with a disease-causing mutation.","method":"Direct sequencing of CCT5 coding exons in affected family members; mutation absent in 384 control chromosomes","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing with familial co-segregation and population controls, single lab","pmids":["16399879"],"is_preprint":false},{"year":2013,"finding":"Human CCT5 expressed alone in E. coli forms homo-oligomeric double-ring complexes (two back-to-back rings of eight subunits, ~20S), hydrolyzes ATP at rates similar to TRiC, and is active in luciferase refolding and γD-crystallin aggregation suppression/refolding assays, demonstrating that CCT5 can carry out chaperonin reactions independent of other CCT subunits.","method":"Recombinant expression in E. coli, sucrose gradient sedimentation, negative-stain and cryo-EM, ATPase assay, luciferase refolding assay, γD-crystallin aggregation suppression and refolding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro biochemical and structural methods (cryo-EM, ATPase, refolding assays) in a single rigorous study","pmids":["23612981"],"is_preprint":false},{"year":2014,"finding":"The H147R CCT5 mutation associated with hereditary sensory neuropathy reduces chaperonin efficiency: H147R CCT5 homo-oligomers show reduced ability to suppress aggregation of γD-crystallin and mutant huntingtin, and to refold β-actin in vitro, while still forming ring structures comparable to wild-type CCT5.","method":"E. coli expression system, sucrose gradient centrifugation, electron microscopy of negatively stained samples, aggregation suppression assay, β-actin refolding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple in vitro functional assays plus structural characterization, single lab with rigorous controls","pmids":["25124038"],"is_preprint":false},{"year":2014,"finding":"The H147R mutation (equivalent to human CCT5 H147R) introduced into an archaeal chaperonin homolog impairs hexadecamer oligomeric assembly, reduces ATPase activity, and causes defective protein homeostasis functions, establishing the molecular basis for how this mutation causes neuropathy.","method":"Archaeal mutant homolog expression system, oligomeric assembly assays, ATPase activity assay, protein homeostasis functional assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution in a proxy system, single lab, multiple orthogonal methods","pmids":["25345891"],"is_preprint":false},{"year":2015,"finding":"The CCT5 homo-oligomeric complex suppresses mutant huntingtin (mHTTQ46-Ex1) aggregation by capping mHTT fibrils at their tips and encapsulating mHTT oligomers, sharing this inhibition mechanism with full TRiC.","method":"Aggregation suppression assay, cryoelectron tomography with computational classification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural cryo-ET combined with functional aggregation assays, rigorous controls comparing to TRiC","pmids":["25995452"],"is_preprint":false},{"year":2017,"finding":"The H147R mutation in CCT5 decouples disassembly of the hexadecamer from subunit denaturation without affecting stability of individual subunits, quantitatively reducing structural stability of the complex as measured by differential scanning calorimetry and isothermal titration calorimetry in the archaeal proxy system.","method":"Differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), archaeal homo-hexadecameric chaperonin proxy system","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical methods in proxy system, single lab","pmids":["29552646"],"is_preprint":false},{"year":2019,"finding":"CCT5 (and CCT2) are required for stabilization of Cdc20, and their depletion reduces Cdc20 levels, reverses p10.8-mediated CDK4 degradation, and blocks p10.8-induced apoptosis, placing CCT5 upstream of Cdc20 in cell cycle and apoptosis regulation.","method":"siRNA-mediated depletion of CCT2 and CCT5, western blot for Cdc20 and CDK4, apoptosis assays in cultured cells","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with defined phenotypic readout and pathway placement, single lab with multiple functional readouts","pmids":["31282373"],"is_preprint":false},{"year":2021,"finding":"CCT5 physically interacts with Cyclin D1 (CCND1) in lung adenocarcinoma cells, and CCT5 knockdown inhibits cell migration and invasion by inactivating the PI3K/AKT pathway and downstream EMT signals, an effect abrogated by CCND1 overexpression.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, in vitro migration/invasion assays, western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional KD assays, single lab, multiple readouts","pmids":["34217974"],"is_preprint":false},{"year":2022,"finding":"CCT5 binds the cytoplasmic domain of E-cadherin and disrupts the E-cadherin/β-catenin interaction, releasing β-catenin to the nucleus and enhancing Wnt/β-catenin signaling activity and EMT, thereby promoting gastric cancer lymph node metastasis.","method":"Co-immunoprecipitation, western blot, qPCR, in vitro functional assays, footpad inoculation mouse xenograft model","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with in vitro and in vivo functional validation, single lab","pmids":["35194191"],"is_preprint":false},{"year":2022,"finding":"CCT5 directly binds the PPV non-structural protein NS1 (via the NS1 N-terminal 36–42 aa motif), promotes viral replication, and mediates the interaction between NS1 and COPΕ; CCT5 depletion reduces NS1-COPΕ interaction and promotes IFN-β expression.","method":"Co-immunoprecipitation, siRNA knockdown, CRISPR/Cas9 knockout, CCT5 overexpression, IFN-β expression assay, PPV replication assay in PK-15 cells","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO, KD, OE, Co-IP), single lab","pmids":["36126504"],"is_preprint":false},{"year":2023,"finding":"DCAF12 (as part of the CRL4DCAF12 E3 ubiquitin ligase) binds the C-terminal di-Glu degron of CCT5 via a positively charged pocket in its WD40 β-propeller; the CCT5 C-terminus is inaccessible in assembled TRiC, so DCAF12 ubiquitinates monomeric CCT5 but not TRiC-assembled CCT5, establishing an assembly quality control mechanism.","method":"Cryo-EM structure of DDB1-DCAF12-CCT5 complex at 2.8 Å, biochemical ubiquitination assays, mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structure plus functional biochemical assays, rigorous controls","pmids":["36715408"],"is_preprint":false},{"year":2023,"finding":"CCT5 (and CCT7) are essential for hematopoietic stem and progenitor cell (HSPC) maintenance; conditional knockout of Cct5 impairs HSPC reconstitution of myeloid and lymphoid lineages in transplantation assays; Cct5 interacts with key transcription factors MYC, PIAS1, TP53, ESR1, HOXA1, and JUN, regulating autophagy, myeloid differentiation, and cytoskeleton organization.","method":"Conditional knockout mouse model, primary and secondary transplantation experiments, PPI database analysis, RNA-seq","journal":"Stem cell reviews and reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined functional reconstitution phenotype; protein-protein interactions inferred from PPI database, not direct biochemical validation","pmids":["38153635"],"is_preprint":false},{"year":2024,"finding":"DCAF12 C-terminal degron peptides of CCT5 form nanomolar affinity interactions with DCAF12 in vitro and in cells; cryo-EM structure of DDB1-DCAF12-MAGEA3 complex at 3.17 Å revealed key DCAF12 residues responsible for C-terminal di-Glu degron recognition (corroborating CCT5 degron recognition mechanism).","method":"Biophysical binding assays, proximity-based cellular NanoBRET assays, cryo-EM structure determination at 3.17 Å","journal":"PNAS nexus","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus orthogonal biophysical and cell-based assays, replicating and extending prior EMBO J findings","pmids":["38665159"],"is_preprint":false},{"year":2024,"finding":"PARK2 (Parkin), an E3 ubiquitin ligase, binds CCT5 and induces its degradation in nasopharyngeal carcinoma cells, acting as an upstream negative modulator of CCT5 protein levels.","method":"Co-immunoprecipitation, western blot, CCT5 overexpression and proliferation assays (EdU, CCK-8)","journal":"The Journal of international medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP result with limited functional follow-up, single lab","pmids":["39286844"],"is_preprint":false},{"year":2025,"finding":"CCT5 and CCT7 are required for telomerase trafficking and TCAB1 protein stability; CCT5 deficiency disrupts telomere length homeostasis, triggers DNA damage response, and induces epigenetic reprogramming promoting 2-cell-like state. Additionally, CCT5 dissociates E-cadherin/β-catenin complexes to stabilize pluripotency through Wnt/β-catenin signaling.","method":"CCT5/CCT7 depletion in ESCs, telomere length measurement, DNA damage response assays, epigenetic profiling, 2-cell transcriptional program activation assays","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple molecular readouts, single lab","pmids":["41455472"],"is_preprint":false},{"year":2025,"finding":"CCT5 directly binds asparagine synthetase (ASNS) and promotes asparagine biosynthesis; the resulting asparagine activates the mTORC1 axis to facilitate tumor cell proliferation and upregulate PD-L1 expression in colorectal cancer.","method":"Co-immunoprecipitation, CRC organoids, patient-derived tumor xenograft (PDX) models, western blot, multifaceted validation assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with in vitro and in vivo functional validation, single lab, multiple orthogonal models","pmids":["40487665"],"is_preprint":false},{"year":2025,"finding":"CCT5 initiates Gβ5 folding through an electrostatic interaction of a single Gβ5 β-strand with the CCT5 subunit; disease-causing missense mutations in Gβ5 disrupt this interaction, causing folding to stall mid-process and leaving Gβ5 in partially folded, non-functional trapped intermediates.","method":"Cryo-EM structure determination of CCT-Gβ5 folding intermediates, biochemical folding assays, mutagenesis","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural visualization of folding trajectory plus biochemical validation and mutagenesis, rigorous mechanistic study","pmids":["bio_10.1101_2025.05.28.656654"],"is_preprint":true},{"year":2026,"finding":"CCT5 interacts with CDC20 and facilitates turnover of the MCC-CDC20-APC/C complex, enabling metaphase-to-anaphase progression; CCT5 silencing impairs proliferation, induces G2/M arrest, and suppresses early colorectal tumor initiation in vivo.","method":"Co-immunoprecipitation, CCT5 genetic depletion, multi-omics profiling, genetically engineered mouse models, cell cycle assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with in vivo genetic depletion and defined cell cycle phenotype, single lab","pmids":["41890968"],"is_preprint":false}],"current_model":"CCT5 is the epsilon subunit of the TRiC/CCT cytosolic chaperonin that folds substrates including actin, tubulin, β-propeller proteins (e.g., Gβ5), and mutant huntingtin in an ATP-dependent manner; it can form functional homo-oligomeric double rings capable of independent chaperonin activity; its C-terminal di-Glu degron is recognized by the CRL4DCAF12 E3 ligase for ubiquitination when CCT5 is monomeric (not assembled into TRiC), providing assembly quality control; the disease-causing H147R mutation reduces chaperonin efficiency and destabilizes the oligomeric complex; CCT5 also participates in multiple non-canonical cellular roles including stabilizing Cdc20 to regulate cell cycle progression, disrupting E-cadherin/β-catenin interactions to activate Wnt/β-catenin signaling, binding asparagine synthetase to promote asparagine biosynthesis, and serving as a folding platform for substrates whose folding trajectory initiates through electrostatic contacts with the CCT5 subunit."},"narrative":{"mechanistic_narrative":"CCT5 is the epsilon subunit of the eukaryotic cytosolic chaperonin TRiC/CCT, an ATP-dependent folding machine, and unlike most CCT subunits it can independently form homo-oligomeric back-to-back double rings that hydrolyze ATP and carry out chaperonin reactions on their own — refolding luciferase and β-actin and suppressing γD-crystallin aggregation [PMID:23612981]. Mechanistically, CCT5 nucleates substrate folding through electrostatic contacts: a single Gβ5 β-strand engages the CCT5 subunit to initiate folding, and disease-linked Gβ5 mutations that disrupt this contact stall folding at trapped intermediates [PMID:bio_10.1101_2025.05.28.656654]. CCT5 homo-oligomers also suppress mutant huntingtin aggregation by capping fibril tips and encapsulating oligomers, mirroring full TRiC [PMID:25995452]. Assembly of CCT5 into TRiC is quality-controlled by the CRL4-DCAF12 E3 ligase, whose WD40 β-propeller recognizes the C-terminal di-Glu degron of CCT5 that is accessible only in monomeric, unassembled CCT5 and buried within assembled TRiC, restricting ubiquitination to free subunits [PMID:36715408, PMID:38665159]. The H147R missense mutation causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia [PMID:16399879]; it destabilizes the oligomeric complex and reduces chaperonin efficiency without denaturing individual subunits [PMID:25124038, PMID:25345891, PMID:29552646]. Beyond folding, CCT5 has been implicated in numerous cellular processes — stabilizing Cdc20 and facilitating MCC-CDC20-APC/C turnover for metaphase-to-anaphase progression [PMID:31282373, PMID:41890968], disrupting E-cadherin/β-catenin complexes to activate Wnt/β-catenin signaling and EMT [PMID:35194191, PMID:41455472], binding asparagine synthetase to drive asparagine biosynthesis and mTORC1 signaling [PMID:40487665], and supporting hematopoietic stem cell maintenance and telomerase trafficking [PMID:38153635, PMID:41455472].","teleology":[{"year":2006,"claim":"Establishing that a CCT subunit mutation can cause inherited human disease, framing CCT5 as medically relevant rather than a purely housekeeping chaperonin component.","evidence":"Direct sequencing of CCT5 exons in an affected family with population controls","pmids":["16399879"],"confidence":"Medium","gaps":["Did not establish the molecular mechanism by which H147R impairs CCT function","Single family; genotype-phenotype relationship not generalized"]},{"year":2013,"claim":"Resolved whether CCT5 requires the other seven CCT subunits to act, demonstrating it can self-assemble into active homo-oligomeric double rings — a surprising autonomy for a hetero-oligomeric chaperonin subunit.","evidence":"Recombinant E. coli expression, cryo-EM, ATPase and refolding/aggregation-suppression assays","pmids":["23612981"],"confidence":"High","gaps":["Whether homo-oligomers form physiologically in cells versus only in recombinant systems","Substrate range of homo-oligomers versus native TRiC not delimited"]},{"year":2014,"claim":"Connected the disease mutation to a functional defect by showing H147R homo-oligomers retain ring architecture but lose folding/aggregation-suppression capacity, and an archaeal proxy showed impaired hexadecamer assembly and ATPase activity.","evidence":"E. coli and archaeal proxy expression, EM, β-actin refolding and aggregation suppression assays, ATPase assays","pmids":["25124038","25345891"],"confidence":"High","gaps":["Mechanistic basis in human TRiC context rather than proxy/homo-oligomer","Link between in vitro folding defect and the specific neuropathy phenotype not demonstrated"]},{"year":2015,"claim":"Defined the structural mechanism by which CCT5 oligomers suppress amyloid aggregation, showing fibril-tip capping and oligomer encapsulation shared with full TRiC.","evidence":"Cryoelectron tomography with computational classification plus aggregation assays of mHTT","pmids":["25995452"],"confidence":"High","gaps":["In vivo relevance to Huntington disease pathology not established","Whether homo-oligomers contribute distinctly from intact TRiC in cells unknown"]},{"year":2017,"claim":"Clarified the thermodynamic nature of the H147R defect, showing it decouples complex disassembly from subunit denaturation rather than destabilizing individual subunits.","evidence":"Differential scanning and isothermal titration calorimetry in archaeal hexadecameric proxy","pmids":["29552646"],"confidence":"Medium","gaps":["Proxy system rather than human CCT5/TRiC","Quantitative stability effect on the native hetero-oligomeric TRiC not measured"]},{"year":2023,"claim":"Revealed how cells perform CCT5 assembly quality control, showing CRL4-DCAF12 recognizes the CCT5 C-terminal di-Glu degron only when it is monomeric, sparing TRiC-assembled CCT5.","evidence":"2.8 Å cryo-EM of DDB1-DCAF12-CCT5, ubiquitination assays, mutagenesis; corroborated by 3.17 Å DCAF12 structure and nanomolar binding assays","pmids":["36715408","38665159"],"confidence":"High","gaps":["In vivo flux of monomeric CCT5 degradation versus assembly not quantified","Whether other CCT subunits share analogous degron-based QC unknown"]},{"year":2024,"claim":"Identified PARK2 (Parkin) as an upstream negative regulator of CCT5 protein levels in a cancer context, extending CCT5 turnover control beyond CRL4-DCAF12.","evidence":"Co-immunoprecipitation, western blot, proliferation assays in nasopharyngeal carcinoma cells","pmids":["39286844"],"confidence":"Low","gaps":["Single Co-IP without reciprocal or structural validation","Direct ubiquitination of CCT5 by Parkin not demonstrated","Specificity for monomeric versus assembled CCT5 not addressed"]},{"year":2025,"claim":"Captured the folding trajectory at single-substrate resolution, showing CCT5 initiates Gβ5 folding via a defined electrostatic β-strand contact and that disease mutations stall folding at trapped intermediates.","evidence":"Cryo-EM of CCT-Gβ5 folding intermediates, folding assays, mutagenesis (preprint)","pmids":["bio_10.1101_2025.05.28.656654"],"confidence":"High","gaps":["Preprint, not peer-reviewed","Generalizability of CCT5-initiated electrostatic folding to other β-propeller substrates not established"]},{"year":2025,"claim":"Expanded CCT5 into non-canonical signaling and metabolic roles — driving asparagine biosynthesis/mTORC1, supporting HSPC maintenance and telomerase trafficking, and modulating Wnt/β-catenin via E-cadherin disruption.","evidence":"Co-IP, conditional/ESC knockouts, organoids, PDX models, transplantation, multi-omics across multiple studies","pmids":["40487665","38153635","41455472","35194191","34217974"],"confidence":"Medium","gaps":["Whether these roles depend on chaperonin folding activity or are moonlighting functions unclear","Several interactions rest on single Co-IP or PPI database inference without structural validation","Directness of binding partners (e.g., MYC, TP53) not biochemically confirmed"]},{"year":2026,"claim":"Linked CCT5 to cell-cycle progression mechanistically, showing it interacts with CDC20 and facilitates MCC-CDC20-APC/C turnover required for metaphase-to-anaphase transition and tumor initiation.","evidence":"Co-IP, genetic depletion, multi-omics, genetically engineered mouse models, cell cycle assays","pmids":["41890968"],"confidence":"Medium","gaps":["Whether CCT5 acts on CDC20 as a chaperonin substrate or via a non-folding mechanism not resolved","Structural basis of CCT5-CDC20 interaction unknown"]},{"year":null,"claim":"It remains unresolved which of CCT5's many non-canonical roles depend on its chaperonin folding activity versus moonlighting functions, and whether homo-oligomeric CCT5 has a physiological role distinct from its function within intact TRiC.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No assay distinguishing folding-dependent from folding-independent CCT5 activities in vivo","Physiological existence and substrate scope of CCT5 homo-oligomers in cells unknown","Mechanism connecting the H147R folding defect to the specific neuropathy phenotype not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[1,2,4,16]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,10,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,17]}],"complexes":["TRiC/CCT chaperonin","CCT5 homo-oligomeric double ring","CRL4-DCAF12 (substrate)"],"partners":["DCAF12","CDC20","CCND1","CDH1 (E-CADHERIN)","ASNS","NS1","PARK2","TCAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48643","full_name":"T-complex protein 1 subunit epsilon","aliases":["CCT-epsilon","Chaperonin containing T-complex polypeptide 1 subunit 5"],"length_aa":541,"mass_kda":59.7,"function":"Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis (PubMed:25467444, PubMed:36493755, PubMed:35449234, PubMed:37193829). The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance (PubMed:25467444). As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia (PubMed:20080638)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/P48643/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCT5","classification":"Common Essential","n_dependent_lines":1203,"n_total_lines":1208,"dependency_fraction":0.9958609271523179},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000150753","cell_line_id":"CID000210","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"ACTB","stoichiometry":10.0},{"gene":"CCT2","stoichiometry":10.0},{"gene":"CCT3","stoichiometry":10.0},{"gene":"CCT4","stoichiometry":10.0},{"gene":"CCT7","stoichiometry":10.0},{"gene":"TCP1","stoichiometry":10.0},{"gene":"CCT8","stoichiometry":10.0},{"gene":"CCT6A","stoichiometry":10.0},{"gene":"PDCD5","stoichiometry":10.0},{"gene":"PPP2CA","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000210","total_profiled":1310},"omim":[{"mim_id":"618568","title":"ATP SYNTHASE C SUBUNIT LYSINE N-METHYLTRANSFERASE; ATPSCKMT","url":"https://www.omim.org/entry/618568"},{"mim_id":"610150","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 5; CCT5","url":"https://www.omim.org/entry/610150"},{"mim_id":"609503","title":"SPERM MICROTUBULE-ASSOCIATED PROTEIN 2; SPMAP2","url":"https://www.omim.org/entry/609503"},{"mim_id":"605140","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 7; CCT7","url":"https://www.omim.org/entry/605140"},{"mim_id":"605139","title":"CHAPERONIN CONTAINING T-COMPLEX POLYPEPTIDE 1, SUBUNIT 2; CCT2","url":"https://www.omim.org/entry/605139"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Additional"},{"location":"Annulus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCT5"},"hgnc":{"alias_symbol":["KIAA0098","CCTE"],"prev_symbol":[]},"alphafold":{"accession":"P48643","domains":[{"cath_id":"1.10.560.10","chopping":"26-153_419-534","consensus_level":"high","plddt":92.9781,"start":26,"end":534},{"cath_id":"3.50.7.10","chopping":"227-379","consensus_level":"high","plddt":89.5921,"start":227,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48643","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48643-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48643-F1-predicted_aligned_error_v6.png","plddt_mean":89.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCT5","jax_strain_url":"https://www.jax.org/strain/search?query=CCT5"},"sequence":{"accession":"P48643","fasta_url":"https://rest.uniprot.org/uniprotkb/P48643.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48643/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48643"}},"corpus_meta":[{"pmid":"16399879","id":"PMC_16399879","title":"Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia.","date":"2006","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16399879","citation_count":107,"is_preprint":false},{"pmid":"35194191","id":"PMC_35194191","title":"CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/β-catenin signalling pathway.","date":"2022","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35194191","citation_count":85,"is_preprint":false},{"pmid":"16821082","id":"PMC_16821082","title":"Possible involvement of CCT5, RGS3, and YKT6 genes up-regulated in p53-mutated tumors in resistance to docetaxel in human breast cancers.","date":"2006","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/16821082","citation_count":69,"is_preprint":false},{"pmid":"23612981","id":"PMC_23612981","title":"Human CCT4 and CCT5 chaperonin subunits expressed in Escherichia coli form biologically active homo-oligomers.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23612981","citation_count":55,"is_preprint":false},{"pmid":"25995452","id":"PMC_25995452","title":"Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25995452","citation_count":34,"is_preprint":false},{"pmid":"25124038","id":"PMC_25124038","title":"Biochemical characterization of mutants in chaperonin proteins CCT4 and CCT5 associated with hereditary sensory neuropathy.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25124038","citation_count":29,"is_preprint":false},{"pmid":"31282373","id":"PMC_31282373","title":"Cdc20 and molecular chaperone CCT2 and CCT5 are required for the Muscovy duck reovirus p10.8-induced cell cycle arrest and apoptosis.","date":"2019","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31282373","citation_count":29,"is_preprint":false},{"pmid":"34217974","id":"PMC_34217974","title":"CCT5 interacts with cyclin D1 promoting lung adenocarcinoma cell migration and invasion.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34217974","citation_count":21,"is_preprint":false},{"pmid":"25345891","id":"PMC_25345891","title":"A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25345891","citation_count":20,"is_preprint":false},{"pmid":"36715408","id":"PMC_36715408","title":"Recognition of the CCT5 di-Glu degron by CRL4DCAF12 is dependent on TRiC assembly.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/36715408","citation_count":19,"is_preprint":false},{"pmid":"33076433","id":"PMC_33076433","title":"A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33076433","citation_count":13,"is_preprint":false},{"pmid":"35720129","id":"PMC_35720129","title":"Muscle Histopathological Abnormalities in a Patient With a CCT5 Mutation Predicted to Affect the Apical Domain of the Chaperonin Subunit.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/35720129","citation_count":8,"is_preprint":false},{"pmid":"36126504","id":"PMC_36126504","title":"Chaperonin CCT5 binding with porcine parvovirus NS1 promotes the interaction of NS1 and COPƐ to facilitate viral replication.","date":"2022","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36126504","citation_count":6,"is_preprint":false},{"pmid":"40487665","id":"PMC_40487665","title":"Inhibition of CCT5-mediated asparagine biosynthesis and anti-PD-L1 produce synergistic antitumor effects in colorectal cancer.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/40487665","citation_count":5,"is_preprint":false},{"pmid":"38665159","id":"PMC_38665159","title":"Probing the CRL4DCAF12 interactions with MAGEA3 and CCT5 di-Glu C-terminal degrons.","date":"2024","source":"PNAS nexus","url":"https://pubmed.ncbi.nlm.nih.gov/38665159","citation_count":5,"is_preprint":false},{"pmid":"29552646","id":"PMC_29552646","title":"Quantitative analysis of the impact of a human pathogenic mutation on the CCT5 chaperonin subunit using a proxy archaeal ortholog.","date":"2017","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/29552646","citation_count":5,"is_preprint":false},{"pmid":"36768350","id":"PMC_36768350","title":"Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768350","citation_count":4,"is_preprint":false},{"pmid":"38153635","id":"PMC_38153635","title":"The Chaperone Protein Cct5 is Essential for Hematopoietic Stem Cell Maintenance.","date":"2023","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/38153635","citation_count":3,"is_preprint":false},{"pmid":"39286844","id":"PMC_39286844","title":"Increased CCT5 expression is a potential unfavourable factor promoting the growth of nasopharyngeal carcinoma.","date":"2024","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/39286844","citation_count":3,"is_preprint":false},{"pmid":"37237456","id":"PMC_37237456","title":"Histopathology of Skeletal Muscle in a Distal Motor Neuropathy Associated with a Mutant CCT5 Subunit: Clues for Future Developments to Improve Differential Diagnosis and Personalized Therapy.","date":"2023","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/37237456","citation_count":1,"is_preprint":false},{"pmid":"41674779","id":"PMC_41674779","title":"TMEM106C, BSG, COPE, CDCA8, KPNA2, LIG1, UQCRH, and CCT5: Predictive of Survival and Immunotherapy Resistance in Hepatocellular Carcinoma.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41674779","citation_count":1,"is_preprint":false},{"pmid":"41455472","id":"PMC_41455472","title":"Chaperonin proteins CCT5 and CCT7 epigenetically restrict the transition from pluripotency to totipotency in embryonic stem cells.","date":"2025","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41455472","citation_count":1,"is_preprint":false},{"pmid":"40928583","id":"PMC_40928583","title":"The oncogenic role of NSUN2 in lung adenocarcinoma by stabilizing CCT5 mRNA via a YBX1-dependent m5C modification.","date":"2025","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40928583","citation_count":0,"is_preprint":false},{"pmid":"41890968","id":"PMC_41890968","title":"CCT5 maintains mitotic fidelity and promotes early colorectal tumorigenesis.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41890968","citation_count":0,"is_preprint":false},{"pmid":"41657783","id":"PMC_41657783","title":"CCT5 as a candidate biomarker in bladder cancer: functional validation and mechanistic clues.","date":"2026","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41657783","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.28.656654","title":"Disease-causing mutations in the G protein β5 β-propeller disrupt its chaperonin-mediated folding trajectory","date":"2025-05-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656654","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15300,"output_tokens":4421,"usd":0.056107,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12403,"output_tokens":3952,"usd":0.080408,"stage2_stop_reason":"end_turn"},"total_usd":0.136515,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"A missense mutation H147R in CCT5 (exon 4, A492G) causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia in humans, identifying CCT5 as the first human CCT subunit gene with a disease-causing mutation.\",\n      \"method\": \"Direct sequencing of CCT5 coding exons in affected family members; mutation absent in 384 control chromosomes\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing with familial co-segregation and population controls, single lab\",\n      \"pmids\": [\"16399879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human CCT5 expressed alone in E. coli forms homo-oligomeric double-ring complexes (two back-to-back rings of eight subunits, ~20S), hydrolyzes ATP at rates similar to TRiC, and is active in luciferase refolding and γD-crystallin aggregation suppression/refolding assays, demonstrating that CCT5 can carry out chaperonin reactions independent of other CCT subunits.\",\n      \"method\": \"Recombinant expression in E. coli, sucrose gradient sedimentation, negative-stain and cryo-EM, ATPase assay, luciferase refolding assay, γD-crystallin aggregation suppression and refolding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro biochemical and structural methods (cryo-EM, ATPase, refolding assays) in a single rigorous study\",\n      \"pmids\": [\"23612981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The H147R CCT5 mutation associated with hereditary sensory neuropathy reduces chaperonin efficiency: H147R CCT5 homo-oligomers show reduced ability to suppress aggregation of γD-crystallin and mutant huntingtin, and to refold β-actin in vitro, while still forming ring structures comparable to wild-type CCT5.\",\n      \"method\": \"E. coli expression system, sucrose gradient centrifugation, electron microscopy of negatively stained samples, aggregation suppression assay, β-actin refolding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple in vitro functional assays plus structural characterization, single lab with rigorous controls\",\n      \"pmids\": [\"25124038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The H147R mutation (equivalent to human CCT5 H147R) introduced into an archaeal chaperonin homolog impairs hexadecamer oligomeric assembly, reduces ATPase activity, and causes defective protein homeostasis functions, establishing the molecular basis for how this mutation causes neuropathy.\",\n      \"method\": \"Archaeal mutant homolog expression system, oligomeric assembly assays, ATPase activity assay, protein homeostasis functional assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution in a proxy system, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25345891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The CCT5 homo-oligomeric complex suppresses mutant huntingtin (mHTTQ46-Ex1) aggregation by capping mHTT fibrils at their tips and encapsulating mHTT oligomers, sharing this inhibition mechanism with full TRiC.\",\n      \"method\": \"Aggregation suppression assay, cryoelectron tomography with computational classification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural cryo-ET combined with functional aggregation assays, rigorous controls comparing to TRiC\",\n      \"pmids\": [\"25995452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The H147R mutation in CCT5 decouples disassembly of the hexadecamer from subunit denaturation without affecting stability of individual subunits, quantitatively reducing structural stability of the complex as measured by differential scanning calorimetry and isothermal titration calorimetry in the archaeal proxy system.\",\n      \"method\": \"Differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), archaeal homo-hexadecameric chaperonin proxy system\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical methods in proxy system, single lab\",\n      \"pmids\": [\"29552646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCT5 (and CCT2) are required for stabilization of Cdc20, and their depletion reduces Cdc20 levels, reverses p10.8-mediated CDK4 degradation, and blocks p10.8-induced apoptosis, placing CCT5 upstream of Cdc20 in cell cycle and apoptosis regulation.\",\n      \"method\": \"siRNA-mediated depletion of CCT2 and CCT5, western blot for Cdc20 and CDK4, apoptosis assays in cultured cells\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with defined phenotypic readout and pathway placement, single lab with multiple functional readouts\",\n      \"pmids\": [\"31282373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCT5 physically interacts with Cyclin D1 (CCND1) in lung adenocarcinoma cells, and CCT5 knockdown inhibits cell migration and invasion by inactivating the PI3K/AKT pathway and downstream EMT signals, an effect abrogated by CCND1 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, in vitro migration/invasion assays, western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional KD assays, single lab, multiple readouts\",\n      \"pmids\": [\"34217974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT5 binds the cytoplasmic domain of E-cadherin and disrupts the E-cadherin/β-catenin interaction, releasing β-catenin to the nucleus and enhancing Wnt/β-catenin signaling activity and EMT, thereby promoting gastric cancer lymph node metastasis.\",\n      \"method\": \"Co-immunoprecipitation, western blot, qPCR, in vitro functional assays, footpad inoculation mouse xenograft model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"35194191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCT5 directly binds the PPV non-structural protein NS1 (via the NS1 N-terminal 36–42 aa motif), promotes viral replication, and mediates the interaction between NS1 and COPΕ; CCT5 depletion reduces NS1-COPΕ interaction and promotes IFN-β expression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, CRISPR/Cas9 knockout, CCT5 overexpression, IFN-β expression assay, PPV replication assay in PK-15 cells\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO, KD, OE, Co-IP), single lab\",\n      \"pmids\": [\"36126504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DCAF12 (as part of the CRL4DCAF12 E3 ubiquitin ligase) binds the C-terminal di-Glu degron of CCT5 via a positively charged pocket in its WD40 β-propeller; the CCT5 C-terminus is inaccessible in assembled TRiC, so DCAF12 ubiquitinates monomeric CCT5 but not TRiC-assembled CCT5, establishing an assembly quality control mechanism.\",\n      \"method\": \"Cryo-EM structure of DDB1-DCAF12-CCT5 complex at 2.8 Å, biochemical ubiquitination assays, mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structure plus functional biochemical assays, rigorous controls\",\n      \"pmids\": [\"36715408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCT5 (and CCT7) are essential for hematopoietic stem and progenitor cell (HSPC) maintenance; conditional knockout of Cct5 impairs HSPC reconstitution of myeloid and lymphoid lineages in transplantation assays; Cct5 interacts with key transcription factors MYC, PIAS1, TP53, ESR1, HOXA1, and JUN, regulating autophagy, myeloid differentiation, and cytoskeleton organization.\",\n      \"method\": \"Conditional knockout mouse model, primary and secondary transplantation experiments, PPI database analysis, RNA-seq\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined functional reconstitution phenotype; protein-protein interactions inferred from PPI database, not direct biochemical validation\",\n      \"pmids\": [\"38153635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DCAF12 C-terminal degron peptides of CCT5 form nanomolar affinity interactions with DCAF12 in vitro and in cells; cryo-EM structure of DDB1-DCAF12-MAGEA3 complex at 3.17 Å revealed key DCAF12 residues responsible for C-terminal di-Glu degron recognition (corroborating CCT5 degron recognition mechanism).\",\n      \"method\": \"Biophysical binding assays, proximity-based cellular NanoBRET assays, cryo-EM structure determination at 3.17 Å\",\n      \"journal\": \"PNAS nexus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus orthogonal biophysical and cell-based assays, replicating and extending prior EMBO J findings\",\n      \"pmids\": [\"38665159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARK2 (Parkin), an E3 ubiquitin ligase, binds CCT5 and induces its degradation in nasopharyngeal carcinoma cells, acting as an upstream negative modulator of CCT5 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, western blot, CCT5 overexpression and proliferation assays (EdU, CCK-8)\",\n      \"journal\": \"The Journal of international medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP result with limited functional follow-up, single lab\",\n      \"pmids\": [\"39286844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT5 and CCT7 are required for telomerase trafficking and TCAB1 protein stability; CCT5 deficiency disrupts telomere length homeostasis, triggers DNA damage response, and induces epigenetic reprogramming promoting 2-cell-like state. Additionally, CCT5 dissociates E-cadherin/β-catenin complexes to stabilize pluripotency through Wnt/β-catenin signaling.\",\n      \"method\": \"CCT5/CCT7 depletion in ESCs, telomere length measurement, DNA damage response assays, epigenetic profiling, 2-cell transcriptional program activation assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple molecular readouts, single lab\",\n      \"pmids\": [\"41455472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT5 directly binds asparagine synthetase (ASNS) and promotes asparagine biosynthesis; the resulting asparagine activates the mTORC1 axis to facilitate tumor cell proliferation and upregulate PD-L1 expression in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, CRC organoids, patient-derived tumor xenograft (PDX) models, western blot, multifaceted validation assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with in vitro and in vivo functional validation, single lab, multiple orthogonal models\",\n      \"pmids\": [\"40487665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT5 initiates Gβ5 folding through an electrostatic interaction of a single Gβ5 β-strand with the CCT5 subunit; disease-causing missense mutations in Gβ5 disrupt this interaction, causing folding to stall mid-process and leaving Gβ5 in partially folded, non-functional trapped intermediates.\",\n      \"method\": \"Cryo-EM structure determination of CCT-Gβ5 folding intermediates, biochemical folding assays, mutagenesis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural visualization of folding trajectory plus biochemical validation and mutagenesis, rigorous mechanistic study\",\n      \"pmids\": [\"bio_10.1101_2025.05.28.656654\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCT5 interacts with CDC20 and facilitates turnover of the MCC-CDC20-APC/C complex, enabling metaphase-to-anaphase progression; CCT5 silencing impairs proliferation, induces G2/M arrest, and suppresses early colorectal tumor initiation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, CCT5 genetic depletion, multi-omics profiling, genetically engineered mouse models, cell cycle assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with in vivo genetic depletion and defined cell cycle phenotype, single lab\",\n      \"pmids\": [\"41890968\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCT5 is the epsilon subunit of the TRiC/CCT cytosolic chaperonin that folds substrates including actin, tubulin, β-propeller proteins (e.g., Gβ5), and mutant huntingtin in an ATP-dependent manner; it can form functional homo-oligomeric double rings capable of independent chaperonin activity; its C-terminal di-Glu degron is recognized by the CRL4DCAF12 E3 ligase for ubiquitination when CCT5 is monomeric (not assembled into TRiC), providing assembly quality control; the disease-causing H147R mutation reduces chaperonin efficiency and destabilizes the oligomeric complex; CCT5 also participates in multiple non-canonical cellular roles including stabilizing Cdc20 to regulate cell cycle progression, disrupting E-cadherin/β-catenin interactions to activate Wnt/β-catenin signaling, binding asparagine synthetase to promote asparagine biosynthesis, and serving as a folding platform for substrates whose folding trajectory initiates through electrostatic contacts with the CCT5 subunit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCT5 is the epsilon subunit of the eukaryotic cytosolic chaperonin TRiC/CCT, an ATP-dependent folding machine, and unlike most CCT subunits it can independently form homo-oligomeric back-to-back double rings that hydrolyze ATP and carry out chaperonin reactions on their own — refolding luciferase and β-actin and suppressing γD-crystallin aggregation [#1]. Mechanistically, CCT5 nucleates substrate folding through electrostatic contacts: a single Gβ5 β-strand engages the CCT5 subunit to initiate folding, and disease-linked Gβ5 mutations that disrupt this contact stall folding at trapped intermediates [#16]. CCT5 homo-oligomers also suppress mutant huntingtin aggregation by capping fibril tips and encapsulating oligomers, mirroring full TRiC [#4]. Assembly of CCT5 into TRiC is quality-controlled by the CRL4-DCAF12 E3 ligase, whose WD40 β-propeller recognizes the C-terminal di-Glu degron of CCT5 that is accessible only in monomeric, unassembled CCT5 and buried within assembled TRiC, restricting ubiquitination to free subunits [#10, #12]. The H147R missense mutation causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia [#0]; it destabilizes the oligomeric complex and reduces chaperonin efficiency without denaturing individual subunits [#2, #3, #5]. Beyond folding, CCT5 has been implicated in numerous cellular processes — stabilizing Cdc20 and facilitating MCC-CDC20-APC/C turnover for metaphase-to-anaphase progression [#6, #17], disrupting E-cadherin/β-catenin complexes to activate Wnt/β-catenin signaling and EMT [#8, #14], binding asparagine synthetase to drive asparagine biosynthesis and mTORC1 signaling [#15], and supporting hematopoietic stem cell maintenance and telomerase trafficking [#11, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that a CCT subunit mutation can cause inherited human disease, framing CCT5 as medically relevant rather than a purely housekeeping chaperonin component.\",\n      \"evidence\": \"Direct sequencing of CCT5 exons in an affected family with population controls\",\n      \"pmids\": [\"16399879\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not establish the molecular mechanism by which H147R impairs CCT function\", \"Single family; genotype-phenotype relationship not generalized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved whether CCT5 requires the other seven CCT subunits to act, demonstrating it can self-assemble into active homo-oligomeric double rings — a surprising autonomy for a hetero-oligomeric chaperonin subunit.\",\n      \"evidence\": \"Recombinant E. coli expression, cryo-EM, ATPase and refolding/aggregation-suppression assays\",\n      \"pmids\": [\"23612981\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether homo-oligomers form physiologically in cells versus only in recombinant systems\", \"Substrate range of homo-oligomers versus native TRiC not delimited\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected the disease mutation to a functional defect by showing H147R homo-oligomers retain ring architecture but lose folding/aggregation-suppression capacity, and an archaeal proxy showed impaired hexadecamer assembly and ATPase activity.\",\n      \"evidence\": \"E. coli and archaeal proxy expression, EM, β-actin refolding and aggregation suppression assays, ATPase assays\",\n      \"pmids\": [\"25124038\", \"25345891\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic basis in human TRiC context rather than proxy/homo-oligomer\", \"Link between in vitro folding defect and the specific neuropathy phenotype not demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the structural mechanism by which CCT5 oligomers suppress amyloid aggregation, showing fibril-tip capping and oligomer encapsulation shared with full TRiC.\",\n      \"evidence\": \"Cryoelectron tomography with computational classification plus aggregation assays of mHTT\",\n      \"pmids\": [\"25995452\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo relevance to Huntington disease pathology not established\", \"Whether homo-oligomers contribute distinctly from intact TRiC in cells unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Clarified the thermodynamic nature of the H147R defect, showing it decouples complex disassembly from subunit denaturation rather than destabilizing individual subunits.\",\n      \"evidence\": \"Differential scanning and isothermal titration calorimetry in archaeal hexadecameric proxy\",\n      \"pmids\": [\"29552646\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Proxy system rather than human CCT5/TRiC\", \"Quantitative stability effect on the native hetero-oligomeric TRiC not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed how cells perform CCT5 assembly quality control, showing CRL4-DCAF12 recognizes the CCT5 C-terminal di-Glu degron only when it is monomeric, sparing TRiC-assembled CCT5.\",\n      \"evidence\": \"2.8 Å cryo-EM of DDB1-DCAF12-CCT5, ubiquitination assays, mutagenesis; corroborated by 3.17 Å DCAF12 structure and nanomolar binding assays\",\n      \"pmids\": [\"36715408\", \"38665159\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo flux of monomeric CCT5 degradation versus assembly not quantified\", \"Whether other CCT subunits share analogous degron-based QC unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PARK2 (Parkin) as an upstream negative regulator of CCT5 protein levels in a cancer context, extending CCT5 turnover control beyond CRL4-DCAF12.\",\n      \"evidence\": \"Co-immunoprecipitation, western blot, proliferation assays in nasopharyngeal carcinoma cells\",\n      \"pmids\": [\"39286844\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single Co-IP without reciprocal or structural validation\", \"Direct ubiquitination of CCT5 by Parkin not demonstrated\", \"Specificity for monomeric versus assembled CCT5 not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Captured the folding trajectory at single-substrate resolution, showing CCT5 initiates Gβ5 folding via a defined electrostatic β-strand contact and that disease mutations stall folding at trapped intermediates.\",\n      \"evidence\": \"Cryo-EM of CCT-Gβ5 folding intermediates, folding assays, mutagenesis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.28.656654\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Generalizability of CCT5-initiated electrostatic folding to other β-propeller substrates not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded CCT5 into non-canonical signaling and metabolic roles — driving asparagine biosynthesis/mTORC1, supporting HSPC maintenance and telomerase trafficking, and modulating Wnt/β-catenin via E-cadherin disruption.\",\n      \"evidence\": \"Co-IP, conditional/ESC knockouts, organoids, PDX models, transplantation, multi-omics across multiple studies\",\n      \"pmids\": [\"40487665\", \"38153635\", \"41455472\", \"35194191\", \"34217974\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether these roles depend on chaperonin folding activity or are moonlighting functions unclear\", \"Several interactions rest on single Co-IP or PPI database inference without structural validation\", \"Directness of binding partners (e.g., MYC, TP53) not biochemically confirmed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked CCT5 to cell-cycle progression mechanistically, showing it interacts with CDC20 and facilitates MCC-CDC20-APC/C turnover required for metaphase-to-anaphase transition and tumor initiation.\",\n      \"evidence\": \"Co-IP, genetic depletion, multi-omics, genetically engineered mouse models, cell cycle assays\",\n      \"pmids\": [\"41890968\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether CCT5 acts on CDC20 as a chaperonin substrate or via a non-folding mechanism not resolved\", \"Structural basis of CCT5-CDC20 interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which of CCT5's many non-canonical roles depend on its chaperonin folding activity versus moonlighting functions, and whether homo-oligomeric CCT5 has a physiological role distinct from its function within intact TRiC.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No assay distinguishing folding-dependent from folding-independent CCT5 activities in vivo\", \"Physiological existence and substrate scope of CCT5 homo-oligomers in cells unknown\", \"Mechanism connecting the H147R folding defect to the specific neuropathy phenotype not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [1, 2, 4, 16]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 10, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"complexes\": [\"TRiC/CCT chaperonin\", \"CCT5 homo-oligomeric double ring\", \"CRL4-DCAF12 (substrate)\"],\n    \"partners\": [\"DCAF12\", \"CDC20\", \"CCND1\", \"CDH1 (E-cadherin)\", \"ASNS\", \"NS1\", \"PARK2\", \"TCAB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}