TCP1

id: P12612
gene_symbol: TCP1
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  TCP1 (also known as CCT1) encodes the alpha subunit of the chaperonin-containing T-complex
  (TRiC/CCT) in S. cerevisiae. TRiC/CCT is an essential, hetero-oligomeric, group II chaperonin
  composed of eight paralogous subunits (CCT1-8) arranged in two stacked rings of eight subunits
  each, forming a ~1 MDa complex. The complex functions as an ATP-dependent protein folding
  machine that assists the folding of actin, tubulin, and a small number of other substrates
  including WD40-repeat proteins. Each subunit contributes to the overall ATP-dependent protein
  folding chaperone activity of the complex; individual subunits do not independently fold
  substrates. TCP1/CCT1 is essential for viability and plays roles in mitotic spindle formation
  in yeast. The crystal structure of yeast CCT (PMID:21701561) reveals intrinsic asymmetry
  among the eight subunits, with each displaying unique configurations and substrate-binding
  properties.
existing_annotations:
# ============================================================
# IBA ANNOTATIONS (phylogenetically inferred)
# ============================================================
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      TCP1 is part of the TRiC/CCT complex that assists protein folding. IBA annotation
      is consistent with IDA evidence from PMID:16762366 demonstrating that purified yeast
      CCT catalyses actin folding in vitro.
    action: ACCEPT
    reason: >-
      Core biological process. The TRiC/CCT complex is an essential protein folding machine,
      and TCP1 is a required subunit. IBA is well supported by experimental data.
    supported_by:
      - reference_id: PMID:16762366
        supporting_text: "The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent protein folding machine whose action is required for folding the cytoskeletal proteins actin and tubulin"
- term:
    id: GO:0005832
    label: chaperonin-containing T-complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      TCP1 is the alpha subunit of the chaperonin-containing T-complex (TRiC/CCT). IBA is
      consistent with IDA and IPI evidence from PMID:16762366 and PMID:15704212.
    action: ACCEPT
    reason: >-
      Core complex membership. TCP1 is an integral, essential subunit of TRiC/CCT.
      Well supported by multiple experimental methods.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is proposed for obsoletion. TCP1, as a subunit
      of TRiC/CCT, does interact with unfolded substrates (actin, tubulin), but this occurs
      in the context of the ATP-dependent chaperonin folding cycle, not as a standalone
      binding function. The correct replacement is GO:0140662 (ATP-dependent protein folding
      chaperone), with the qualifier contributes_to since TCP1 is a subunit of the complex.
    action: MODIFY
    reason: >-
      GO:0051082 is targeted for obsoletion. TCP1 binds unfolded proteins only as part of
      the TRiC/CCT complex's ATP-dependent folding cycle. The appropriate replacement is
      GO:0140662 (ATP-dependent protein folding chaperone). This IEA-level annotation via
      InterPro already exists for this gene.
    proposed_replacement_terms:
      - id: GO:0140662
        label: ATP-dependent protein folding chaperone
# ============================================================
# IEA ANNOTATIONS (computationally inferred)
# ============================================================
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      TCP1 binds ATP as part of its chaperonin function. This is a parent term of ATP binding
      and is correct but general.
    action: ACCEPT
    reason: >-
      Correct. All TRiC/CCT subunits bind nucleotides (ATP/ADP). The more specific term
      ATP binding (GO:0005524) is also annotated. This broader IEA is acceptable.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      TCP1 binds ATP through its equatorial domain. Each CCT subunit has an ATP-binding
      site that is essential for the allosteric chaperonin cycle.
    action: ACCEPT
    reason: >-
      Correct and fundamental. ATP binding is essential for the TRiC/CCT folding mechanism.
      UniProt keywords confirm ATP-binding.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      TCP1 is a cytoplasmic protein. UniProt subcellular location annotation confirms
      cytoplasmic localization.
    action: ACCEPT
    reason: >-
      Correct. TRiC/CCT is a cytoplasmic/cytosolic complex.
- term:
    id: GO:0005832
    label: chaperonin-containing T-complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      Redundant with the IBA and IDA annotations for TRiC/CCT membership. Correct ARBA-based
      annotation.
    action: ACCEPT
    reason: >-
      Correct. Redundant with experimental evidence but acceptable.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Redundant with IBA and IDA annotations for protein folding. Correct.
    action: ACCEPT
    reason: >-
      Correct. Consistent with IBA and IDA evidence.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Each TRiC/CCT subunit has ATPase activity. The crystal structure (PMID:21701561)
      reveals ATP-binding heterogeneity among subunits, and the complex uses a sequential
      ATP hydrolysis mechanism.
    action: ACCEPT
    reason: >-
      Correct. Each CCT subunit contributes ATPase activity to the chaperonin cycle.
      InterPro-based annotation is well supported.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      GO:0051082 is proposed for obsoletion. Same rationale as the IBA annotation above.
    action: MODIFY
    reason: >-
      GO:0051082 is targeted for obsoletion. Should be replaced with GO:0140662
      (ATP-dependent protein folding chaperone), which is already annotated via InterPro.
    proposed_replacement_terms:
      - id: GO:0140662
        label: ATP-dependent protein folding chaperone
- term:
    id: GO:0140662
    label: ATP-dependent protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      This is the correct molecular function term for TRiC/CCT subunits. InterPro-based
      annotation via IPR017998 (Chaperone TCP-1). TCP1 contributes to this activity as
      part of the hetero-oligomeric complex.
    action: ACCEPT
    reason: >-
      Correct and the most appropriate MF term. GO:0140662 is the proper replacement for
      the obsoleting GO:0051082. As a complex subunit, the qualifier should ideally be
      contributes_to rather than enables, but the IEA annotation is correct in substance.
# ============================================================
# IPI ANNOTATIONS (protein binding)
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554755
  review:
    summary: >-
      IPI evidence from the global landscape of protein complexes study (Krogan et al. 2006).
      TCP1 interacts with POP2 (P39008) and YPP1 (P46951) in TAP-MS experiments.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative for a chaperonin subunit. Interactions detected in
      large-scale complex purification studies likely reflect chaperone-substrate or
      complex-subunit interactions already captured by the TRiC/CCT complex membership
      annotation. These are better described by the chaperonin complex annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19536198
  review:
    summary: >-
      IPI evidence from the chaperone-protein interactions atlas (Gong et al. 2009).
      TCP1 interacts with SIT4 (P20604), POP2 (P39008), and YPP1 (P46951).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative for a chaperonin subunit. These interactions
      represent chaperonin-substrate relationships that are an inherent part of TRiC/CCT
      function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20489023
  review:
    summary: >-
      IPI evidence from a global protein kinase and phosphatase interaction network.
      TCP1 interacts with SIT4 (P20604).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative for a chaperonin subunit.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21701561
  review:
    summary: >-
      IPI evidence from the crystal structure study of yeast CCT. TCP1 interacts with
      ACT1 (P60010) in the CCT-actin co-crystal structure. This is a well-characterized
      chaperonin-substrate interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative. The TCP1-actin interaction is a direct
      chaperonin-substrate relationship, which is the core function of TRiC/CCT
      already captured by the protein folding and complex membership annotations.
    supported_by:
      - reference_id: PMID:21701561
        supporting_text: "We have solved the crystal structure of yeast CCT in complex with actin at 3.8 Å resolution, revealing the subunit organisation and the location of discrete patches of co-evolving 'signature residues' that mediate specific interactions between CCT and its substrates."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107014
  review:
    summary: >-
      IPI evidence from an inter-species protein-protein interaction network. TCP1 interacts
      with several human proteins (cross-species interactions).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative. Cross-species interactions in this context
      likely reflect conserved chaperonin-substrate relationships.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37968396
  review:
    summary: >-
      IPI evidence from the social and structural architecture of the yeast protein
      interactome. TCP1 interacts with SIT4 (P20604).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative for a chaperonin subunit.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9878052
  review:
    summary: >-
      IPI evidence from the chaperonin-GimC system study (Siegers et al. 1999). TCP1
      interacts with ACT1 (P60010). This study demonstrated that TRiC and GimC form an
      integrated folding compartment that sequesters newly synthesized actin.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative. The TCP1-actin interaction is a core
      chaperonin-substrate relationship already captured by the protein folding and
      complex annotations. The study supports the chaperonin function annotation.
    supported_by:
      - reference_id: PMID:9878052
        supporting_text: "We propose that TRiC and GimC form an integrated 'folding compartment' which functions in cooperation with the translation machinery."
# ============================================================
# IDA ANNOTATIONS (direct experimental evidence)
# ============================================================
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:16762366
  review:
    summary: >-
      PMID:16762366 demonstrated quantitative actin folding using purified yeast CCT.
      The purified complex catalyses folding of both yeast ACT1p and human beta-actin
      with nearly identical rate constants.
    action: ACCEPT
    reason: >-
      Core biological process. Direct experimental demonstration of TRiC/CCT-mediated
      protein folding in vitro using the purified complex containing TCP1.
    supported_by:
      - reference_id: PMID:16762366
        supporting_text: "Yeast CCT catalyses the folding of yeast ACT1p and human beta-actin with nearly identical rate constants and yields."
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: HDA
  original_reference_id: PMID:16622836
  review:
    summary: >-
      HDA evidence from the plasma membrane proteome study. TCP1 was detected in the
      plasma membrane fraction, though this may reflect co-purification rather than
      true membrane localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      TCP1 was detected in the plasma membrane proteome, but TRiC/CCT is primarily
      a cytosolic complex. The plasma membrane association may be a minor or
      artifact localization. Not a core localization.
- term:
    id: GO:0005832
    label: chaperonin-containing T-complex
  evidence_type: IPI
  original_reference_id: PMID:15704212
  review:
    summary: >-
      PMID:15704212 studied physiological effects of unassembled Cct subunits. TCP1
      was shown to be part of the complex through interaction with other subunits
      (with CCT6/S000002596 as supporting entity).
    action: ACCEPT
    reason: >-
      Core complex membership with experimental IPI evidence.
    supported_by:
      - reference_id: PMID:15704212
        supporting_text: "Eukaryotic chaperonins, the Cct complexes, are assembled into two rings, each of which is composed of a stoichiometric array of eight different subunits"
- term:
    id: GO:0005832
    label: chaperonin-containing T-complex
  evidence_type: IDA
  original_reference_id: PMID:16762366
  review:
    summary: >-
      PMID:16762366 purified the intact yeast CCT complex, confirming TCP1 as a
      constituent subunit.
    action: ACCEPT
    reason: >-
      Core complex membership with direct experimental evidence from purified complex.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:16762366
  review:
    summary: >-
      GO:0051082 is proposed for obsoletion. PMID:16762366 demonstrated that the purified
      CCT complex binds actin folding intermediates (Ac(I)) and processes them to native
      actin in an ATP-dependent manner. This is chaperonin-mediated folding, not passive
      unfolded protein binding.
    action: MODIFY
    reason: >-
      GO:0051082 is targeted for obsoletion. The experimental evidence from PMID:16762366
      actually demonstrates ATP-dependent protein folding chaperone activity. The CCT complex
      binds actin intermediates in a pre-equilibrium step followed by ATP-driven processing
      to native actin. This is GO:0140662 (ATP-dependent protein folding chaperone).
    proposed_replacement_terms:
      - id: GO:0140662
        label: ATP-dependent protein folding chaperone
    supported_by:
      - reference_id: PMID:16762366
        supporting_text: "The results from this controlled CCT-actin folding assay are consistent with a model where CCT and Ac(I) are in a binding pre-equilibrium with a rate-limiting binding step, followed by a faster ATP-driven processing to native actin."
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15704212
  title: Physiological effects of unassembled chaperonin Cct subunits in the yeast
    Saccharomyces cerevisiae.
  findings:
    - statement: Studied physiological effects of overexpressing individual CCT subunits
      supporting_text: "Overexpression of a single CCT gene in Saccharomyces cerevisiae causes an increase of the corresponding Cct subunit, but not of the Cct complex."
    - statement: Showed that CCT subunits form a stoichiometric array of eight different subunits in two rings
      supporting_text: "Eukaryotic chaperonins, the Cct complexes, are assembled into two rings, each of which is composed of a stoichiometric array of eight different subunits"
- id: PMID:16554755
  title: Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
  findings: []
- id: PMID:16622836
  title: The plasma membrane proteome of Saccharomyces cerevisiae and its response
    to the antifungal calcofluor.
  findings: []
- id: PMID:16762366
  title: Quantitative actin folding reactions using yeast CCT purified via an internal
    tag in the CCT3/gamma subunit.
  findings:
    - statement: Developed efficient purification protocol for yeast CCT
      supporting_text: "An efficient purification protocol for CCT from Saccharomyces cerevisiae has been developed."
    - statement: Demonstrated quantitative actin folding by purified yeast CCT in vitro
      supporting_text: "Yeast CCT catalyses the folding of yeast ACT1p and human beta-actin with nearly identical rate constants and yields."
    - statement: CCT catalyses folding via a binding pre-equilibrium followed by ATP-driven processing
      supporting_text: "The results from this controlled CCT-actin folding assay are consistent with a model where CCT and Ac(I) are in a binding pre-equilibrium with a rate-limiting binding step, followed by a faster ATP-driven processing to native actin."
- id: PMID:19536198
  title: 'An atlas of chaperone-protein interactions in Saccharomyces cerevisiae:
    implications to protein folding pathways in the cell.'
  findings: []
- id: PMID:20489023
  title: A global protein kinase and phosphatase interaction network in yeast.
  findings: []
- id: PMID:21701561
  title: The crystal structure of yeast CCT reveals intrinsic asymmetry of eukaryotic
    cytosolic chaperonins.
  findings:
    - statement: Solved crystal structure of yeast CCT in complex with actin at 3.8 Å
      supporting_text: "We have solved the crystal structure of yeast CCT in complex with actin at 3.8 Å resolution, revealing the subunit organisation and the location of discrete patches of co-evolving 'signature residues' that mediate specific interactions between CCT and its substrates."
    - statement: Revealed intrinsic asymmetry and subunit individuality in the complex
      supporting_text: "The intrinsic asymmetry is revealed by the structural individuality of the CCT subunits, which display unique configurations, substrate binding properties, ATP-binding heterogeneity and subunit-subunit interactions."
    - statement: CCT uses a sequential rather than concerted ATP hydrolysis mechanism
      supporting_text: "the mechanism by which CCT assists folding is distinct from other chaperonins, with no hydrophobic wall lining a potential Anfinsen cage, and a sequential rather than concerted ATP hydrolysis mechanism."
- id: PMID:27107014
  title: An inter-species protein-protein interaction network across vast evolutionary
    distance.
  findings: []
- id: PMID:37968396
  title: The social and structural architecture of the yeast protein interactome.
  findings: []
- id: PMID:9878052
  title: 'Compartmentation of protein folding in vivo: sequestration of non-native
    polypeptide by the chaperonin-GimC system.'
  findings:
    - statement: TRiC and GimC form an integrated folding compartment for newly synthesized actin
      supporting_text: "We propose that TRiC and GimC form an integrated 'folding compartment' which functions in cooperation with the translation machinery."
    - statement: GimC accelerates actin folding on TRiC at least 5-fold
      supporting_text: "GimC accelerates actin folding at least 5-fold and prevents the premature release of non-native protein from TRiC."
core_functions:
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    contributes_to_molecular_function:
      id: GO:0140662
      label: ATP-dependent protein folding chaperone
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005737
        label: cytoplasm
    in_complex:
      id: GO:0005832
      label: chaperonin-containing T-complex
    description: >-
      TCP1 is the alpha subunit of the TRiC/CCT chaperonin complex. It contributes to the
      complex-level ATP-dependent protein folding chaperone activity (GO:0140662) that folds
      actin, tubulin, and other substrates. Individual subunits do not independently fold
      substrates; the activity emerges from the assembled hetero-oligomeric complex. The
      crystal structure (PMID:21701561) reveals that each subunit has unique configurations
      and substrate-binding properties, suggesting specialized roles within the complex.
      TCP1 binds ATP and contributes ATPase activity to the sequential ATP hydrolysis
      mechanism that drives the chaperonin cycle.
    supported_by:
      - reference_id: PMID:16762366
        supporting_text: "The eukaryotic cytosolic chaperonin CCT is an essential ATP-dependent protein folding machine whose action is required for folding the cytoskeletal proteins actin and tubulin"
      - reference_id: PMID:21701561
        supporting_text: "The cytosolic chaperonin CCT is a 1-MDa protein-folding machine essential for eukaryotic life."