Affinage

CCT5

T-complex protein 1 subunit epsilon · UniProt P48643

Length
541 aa
Mass
59.7 kDa
Annotated
2026-06-09
25 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2006 Medium

    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

    PMID:16399879

    Open questions at the time
    • Did not establish the molecular mechanism by which H147R impairs CCT function
    • Single family; genotype-phenotype relationship not generalized
  2. 2013 High

    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

    PMID:23612981

    Open questions at the time
    • Whether homo-oligomers form physiologically in cells versus only in recombinant systems
    • Substrate range of homo-oligomers versus native TRiC not delimited
  3. 2014 High

    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

    PMID:25124038 PMID:25345891

    Open questions at the time
    • Mechanistic basis in human TRiC context rather than proxy/homo-oligomer
    • Link between in vitro folding defect and the specific neuropathy phenotype not demonstrated
  4. 2015 High

    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

    PMID:25995452

    Open questions at the time
    • In vivo relevance to Huntington disease pathology not established
    • Whether homo-oligomers contribute distinctly from intact TRiC in cells unknown
  5. 2017 Medium

    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

    PMID:29552646

    Open questions at the time
    • Proxy system rather than human CCT5/TRiC
    • Quantitative stability effect on the native hetero-oligomeric TRiC not measured
  6. 2023 High

    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

    PMID:36715408 PMID:38665159

    Open questions at the time
    • In vivo flux of monomeric CCT5 degradation versus assembly not quantified
    • Whether other CCT subunits share analogous degron-based QC unknown
  7. 2024 Low

    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

    PMID:39286844

    Open questions at the time
    • Single Co-IP without reciprocal or structural validation
    • Direct ubiquitination of CCT5 by Parkin not demonstrated
    • Specificity for monomeric versus assembled CCT5 not addressed
  8. 2025 High

    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)

    PMID:bio_10.1101_2025.05.28.656654

    Open questions at the time
    • Preprint, not peer-reviewed
    • Generalizability of CCT5-initiated electrostatic folding to other β-propeller substrates not established
  9. 2025 Medium

    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

    PMID:34217974 PMID:35194191 PMID:38153635 PMID:40487665 PMID:41455472

    Open questions at the time
    • 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
  10. 2026 Medium

    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

    PMID:41890968

    Open questions at the time
    • Whether CCT5 acts on CDC20 as a chaperonin substrate or via a non-folding mechanism not resolved
    • Structural basis of CCT5-CDC20 interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2
Partners
ASNSCCND1CDC20CDH1 (E-CADHERIN)DCAF12NS1PARK2TCAB1
Complex memberships
CCT5 homo-oligomeric double ringCRL4-DCAF12 (substrate)TRiC/CCT chaperonin

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. Direct sequencing of CCT5 coding exons in affected family members; mutation absent in 384 control chromosomes Journal of medical genetics Medium 16399879
2013 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. 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 The Journal of biological chemistry High 23612981
2014 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. E. coli expression system, sucrose gradient centrifugation, electron microscopy of negatively stained samples, aggregation suppression assay, β-actin refolding assay The Journal of biological chemistry High 25124038
2014 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. Archaeal mutant homolog expression system, oligomeric assembly assays, ATPase activity assay, protein homeostasis functional assays Scientific reports Medium 25345891
2015 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. Aggregation suppression assay, cryoelectron tomography with computational classification The Journal of biological chemistry High 25995452
2017 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. Differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), archaeal homo-hexadecameric chaperonin proxy system Biochemistry and biophysics reports Medium 29552646
2019 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. siRNA-mediated depletion of CCT2 and CCT5, western blot for Cdc20 and CDK4, apoptosis assays in cultured cells Veterinary microbiology Medium 31282373
2021 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. Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, in vitro migration/invasion assays, western blot Biochemical and biophysical research communications Medium 34217974
2022 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. Co-immunoprecipitation, western blot, qPCR, in vitro functional assays, footpad inoculation mouse xenograft model British journal of cancer Medium 35194191
2022 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. Co-immunoprecipitation, siRNA knockdown, CRISPR/Cas9 knockout, CCT5 overexpression, IFN-β expression assay, PPV replication assay in PK-15 cells Veterinary microbiology Medium 36126504
2023 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. Cryo-EM structure of DDB1-DCAF12-CCT5 complex at 2.8 Å, biochemical ubiquitination assays, mutagenesis The EMBO journal High 36715408
2023 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. Conditional knockout mouse model, primary and secondary transplantation experiments, PPI database analysis, RNA-seq Stem cell reviews and reports Medium 38153635
2024 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). Biophysical binding assays, proximity-based cellular NanoBRET assays, cryo-EM structure determination at 3.17 Å PNAS nexus High 38665159
2024 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. Co-immunoprecipitation, western blot, CCT5 overexpression and proliferation assays (EdU, CCK-8) The Journal of international medical research Low 39286844
2025 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. CCT5/CCT7 depletion in ESCs, telomere length measurement, DNA damage response assays, epigenetic profiling, 2-cell transcriptional program activation assays Stem cell reports Medium 41455472
2025 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. Co-immunoprecipitation, CRC organoids, patient-derived tumor xenograft (PDX) models, western blot, multifaceted validation assays Acta pharmaceutica Sinica. B Medium 40487665
2025 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. Cryo-EM structure determination of CCT-Gβ5 folding intermediates, biochemical folding assays, mutagenesis bioRxivpreprint High bio_10.1101_2025.05.28.656654
2026 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. Co-immunoprecipitation, CCT5 genetic depletion, multi-omics profiling, genetically engineered mouse models, cell cycle assays iScience Medium 41890968

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 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. Journal of medical genetics 107 16399879
2022 CCT5 induces epithelial-mesenchymal transition to promote gastric cancer lymph node metastasis by activating the Wnt/β-catenin signalling pathway. British journal of cancer 85 35194191
2006 Possible involvement of CCT5, RGS3, and YKT6 genes up-regulated in p53-mutated tumors in resistance to docetaxel in human breast cancers. Breast cancer research and treatment 69 16821082
2013 Human CCT4 and CCT5 chaperonin subunits expressed in Escherichia coli form biologically active homo-oligomers. The Journal of biological chemistry 55 23612981
2015 Structural Mechanisms of Mutant Huntingtin Aggregation Suppression by the Synthetic Chaperonin-like CCT5 Complex Explained by Cryoelectron Tomography. The Journal of biological chemistry 34 25995452
2019 Cdc20 and molecular chaperone CCT2 and CCT5 are required for the Muscovy duck reovirus p10.8-induced cell cycle arrest and apoptosis. Veterinary microbiology 29 31282373
2014 Biochemical characterization of mutants in chaperonin proteins CCT4 and CCT5 associated with hereditary sensory neuropathy. The Journal of biological chemistry 29 25124038
2021 CCT5 interacts with cyclin D1 promoting lung adenocarcinoma cell migration and invasion. Biochemical and biophysical research communications 21 34217974
2014 A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model. Scientific reports 20 25345891
2023 Recognition of the CCT5 di-Glu degron by CRL4DCAF12 is dependent on TRiC assembly. The EMBO journal 19 36715408
2020 A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy. International journal of molecular sciences 13 33076433
2022 Muscle Histopathological Abnormalities in a Patient With a CCT5 Mutation Predicted to Affect the Apical Domain of the Chaperonin Subunit. Frontiers in molecular biosciences 8 35720129
2022 Chaperonin CCT5 binding with porcine parvovirus NS1 promotes the interaction of NS1 and COPƐ to facilitate viral replication. Veterinary microbiology 6 36126504
2025 Inhibition of CCT5-mediated asparagine biosynthesis and anti-PD-L1 produce synergistic antitumor effects in colorectal cancer. Acta pharmaceutica Sinica. B 5 40487665
2024 Probing the CRL4DCAF12 interactions with MAGEA3 and CCT5 di-Glu C-terminal degrons. PNAS nexus 5 38665159
2017 Quantitative analysis of the impact of a human pathogenic mutation on the CCT5 chaperonin subunit using a proxy archaeal ortholog. Biochemistry and biophysics reports 5 29552646
2023 Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies. International journal of molecular sciences 4 36768350
2024 Increased CCT5 expression is a potential unfavourable factor promoting the growth of nasopharyngeal carcinoma. The Journal of international medical research 3 39286844
2023 The Chaperone Protein Cct5 is Essential for Hematopoietic Stem Cell Maintenance. Stem cell reviews and reports 3 38153635
2026 TMEM106C, BSG, COPE, CDCA8, KPNA2, LIG1, UQCRH, and CCT5: Predictive of Survival and Immunotherapy Resistance in Hepatocellular Carcinoma. Human mutation 1 41674779
2025 Chaperonin proteins CCT5 and CCT7 epigenetically restrict the transition from pluripotency to totipotency in embryonic stem cells. Stem cell reports 1 41455472
2023 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. Biology 1 37237456
2026 CCT5 as a candidate biomarker in bladder cancer: functional validation and mechanistic clues. American journal of cancer research 0 41657783
2026 CCT5 maintains mitotic fidelity and promotes early colorectal tumorigenesis. iScience 0 41890968
2025 The oncogenic role of NSUN2 in lung adenocarcinoma by stabilizing CCT5 mRNA via a YBX1-dependent m5C modification. Molecular and cellular biochemistry 0 40928583

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