id: P61758
gene_symbol: VBP1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  VBP1 (von Hippel-Lindau binding protein 1, also known as PFDN3) encodes an
  alpha-type subunit of the heterohexameric prefoldin complex. The prefoldin complex
  is a jellyfish-shaped molecular chaperone composed of two alpha subunits (PFDN3/VBP1
  and PFDN5) and four beta subunits (PFDN1, PFDN2, PFDN4, PFDN6). Prefoldin functions
  as a co-chaperone/holdase that captures unfolded nascent polypeptides -- primarily
  actin and tubulin -- and delivers them to the TRiC/CCT chaperonin for ATP-dependent
  folding. VBP1 was originally identified through its binding to pVHL (the von
  Hippel-Lindau tumor suppressor), and as part of the prefoldin complex it helps
  prevent pVHL aggregation and supports its maturation, thereby contributing to
  HIF-alpha degradation. Beyond its canonical cytoplasmic role, prefoldin has nuclear
  functions influencing transcription elongation and co-transcriptional splicing.
  VBP1 is ubiquitously expressed and located on the X chromosome.
alternative_products:
- name: '1'
  id: P61758-1
- name: '2'
  id: P61758-2
  sequence_note: VSP_060081
existing_annotations:
# ============================================================
# IBA annotations (phylogenetically inferred)
# ============================================================
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0005737 "cytoplasm" is an appropriate cellular component annotation for VBP1.
      This IBA annotation was inferred from phylogenetic analysis (PANTHER) with
      evidence from Drosophila (FB:FBgn0264694), yeast (SGD:S000003310), Arabidopsis,
      C. elegans, and human VBP1 itself. The prefoldin complex is a cytoplasmic
      chaperone that operates in the cytosol to capture unfolded nascent polypeptides
      and deliver them to the cytosolic chaperonin TRiC/CCT (PMID:9630229). Liang
      et al. 2020 (PMID:32699605) describe prefoldin as "a cytoplasmic chaperone
      protein." The term "cytoplasm" is appropriately broad, as a more specific CC
      annotation to "prefoldin complex" (GO:0016272) is already present. Having both
      is correct: one describes subcellular location and the other describes complex
      membership.
    action: ACCEPT
    reason: >-
      VBP1 operates as part of the cytoplasmic prefoldin complex. The cytoplasm
      annotation is well-supported and appropriately broad, complementing the more
      specific prefoldin complex (GO:0016272) annotation. The IBA phylogenetic
      inference is sound (PMID:9630229, PMID:32699605).
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers
        target proteins to it.
    - reference_id: PMID:32699605
      supporting_text: >-
        As a cytoplasmic chaperone protein, the prefoldin complex is a hybrid
        oligomer assembled from six different proteins (six subunits).
- term:
    id: GO:0007017
    label: microtubule-based process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0007017 "microtubule-based process" is a well-supported biological process
      annotation for VBP1. This IBA annotation was inferred from phylogenetic analysis
      (PANTHER) with evidence from Drosophila and Arabidopsis orthologs. The prefoldin
      complex delivers unfolded tubulin to TRiC/CCT for folding, and loss of prefoldin
      subunits disrupts microtubule dynamics and cytoskeletal homeostasis
      (PMID:9630229). Vainberg et al. 1998 showed that "Deletion of the gene encoding
      a prefoldin subunit in S. cerevisiae results in a phenotype similar to those
      found when c-cpn is mutated, namely impaired functions of the actin and
      tubulin-based cytoskeleton." This is a direct consequence of the prefoldin
      chaperone function rather than a core process per se, but it is a well-established
      downstream effect.
    action: ACCEPT
    reason: >-
      Microtubule-based process is a well-established downstream consequence of
      prefoldin's role in tubulin folding. The IBA annotation is phylogenetically
      well-supported, with evidence from yeast genetic studies showing that prefoldin
      loss impairs tubulin-based cytoskeleton function (PMID:9630229).
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results
        in a phenotype similar to those found when c-cpn is mutated, namely impaired
        functions of the actin and tubulin-based cytoskeleton.
- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0016272 "prefoldin complex" is an unambiguous and well-supported CC
      annotation. VBP1 (PFDN3) is one of the two alpha subunits of the heterohexameric
      prefoldin complex (PMID:9630229, PMID:32699605). This IBA annotation was inferred
      from phylogenetic analysis with evidence from Drosophila, yeast, and human VBP1
      itself. Structural data from cryo-EM (PMID:30955883, PDB: 6NR8, 7WU7) directly
      shows VBP1 as a structural component of the human prefoldin complex. The complex
      is also registered in ComplexPortal as CPX-6149 and CPX-25767.
    action: ACCEPT
    reason: >-
      VBP1 is a core structural alpha subunit of the prefoldin complex. This is
      the defining complex membership for VBP1. The IBA annotation is phylogenetically
      well-supported and confirmed by multiple independent experimental studies
      (PMID:9630229, PMID:30955883, PMID:23614719).
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        We describe the discovery of a heterohexameric chaperone protein, prefoldin,
        based on its ability to capture unfolded actin.
    - reference_id: PMID:30955883
      supporting_text: >-
        Maintaining proteostasis in eukaryotic protein folding involves cooperation
        of distinct chaperone systems. To understand how the essential ring-shaped
        chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we
        integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry
        and biochemical and cellular approaches to elucidate the structural and
        functional interplay between TRiC/CCT and PFD.
- term:
    id: GO:0007021
    label: tubulin complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0007021 "tubulin complex assembly" is supported by the canonical function
      of the prefoldin complex. This IBA annotation was inferred from phylogenetic
      analysis with evidence from yeast (SGD:S000003310). The prefoldin complex
      captures nascent tubulin monomers and delivers them to TRiC/CCT for folding,
      which is a prerequisite for tubulin heterodimer assembly (PMID:9630229).
      Vainberg et al. 1998 showed prefoldin promotes tubulin folding, and deletion
      of prefoldin subunit genes in yeast results in impaired tubulin-based
      cytoskeleton function. This is a core function of all prefoldin subunits.
    action: ACCEPT
    reason: >-
      Tubulin complex assembly is a direct consequence of the prefoldin complex's
      chaperone function in delivering unfolded tubulin to TRiC/CCT. The IBA
      annotation is phylogenetically well-supported (PMID:9630229).
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        We describe the discovery of a heterohexameric chaperone protein, prefoldin,
        based on its ability to capture unfolded actin. Prefoldin binds specifically
        to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
- term:
    id: GO:0015631
    label: tubulin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0015631 "tubulin binding" reflects the canonical substrate specificity of
      the prefoldin complex. This IBA annotation was inferred from phylogenetic
      analysis with evidence from Drosophila and yeast. The prefoldin complex binds
      unfolded tubulin monomers and delivers them to TRiC/CCT (PMID:9630229).
      However, tubulin binding is a consequence of the broader protein folding
      chaperone function, and the prefoldin complex also binds actin and other
      substrates including VHL. The annotation is correct but represents a substrate
      specificity rather than a mechanistic function.
    action: ACCEPT
    reason: >-
      Tubulin binding is a well-established substrate specificity of the prefoldin
      complex. The IBA annotation is phylogenetically well-supported and consistent
      with the seminal characterization of prefoldin (PMID:9630229). While somewhat
      reductionist (prefoldin also binds actin and other substrates), tubulin is one
      of the primary substrates and this annotation captures an important specificity.
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results
        in a phenotype similar to those found when c-cpn is mutated, namely impaired
        functions of the actin and tubulin-based cytoskeleton.
# ============================================================
# IEA annotations (electronic)
# ============================================================
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      GO:0005634 "nucleus" was inferred electronically from the UniProt subcellular
      location annotation for VBP1. The UniProt record states "Cytoplasm. Nucleus.
      Note=In complex with VHL can translocate to the nucleus." Nuclear localization
      of VBP1/prefoldin has been confirmed by multiple studies showing that prefoldin
      subunits localize to transcribed chromatin and modulate RNA Pol II CTD
      phosphorylation and co-transcriptional splicing (Payan-Bravo et al. 2021,
      PMID:32699605). VBP1 can also translocate to the nucleus in complex with VHL
      (PMID:8674032). This annotation is consistent with known biology.
    action: ACCEPT
    reason: >-
      Nuclear localization of VBP1 is supported by both the VHL-dependent nuclear
      translocation described in the original VBP1 discovery paper (PMID:8674032) and
      the nuclear functions of prefoldin in transcription/splicing regulation described
      in recent studies (PMID:32699605). The IEA annotation is accurate.
    supported_by:
    - reference_id: PMID:32699605
      supporting_text: >-
        The prefoldin complex helps protein fold correctly and prevents aggregation
        by providing class II chaperones (Hsp60 molecular chaperones found in
        archaebacteria and eukaryotic cytoplasm) with a linear, unnatural substrate
        in the cytoplasm
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      GO:0005737 "cytoplasm" was inferred electronically by the combined automated
      annotation pipeline. This is consistent with the IBA annotation to the same
      term and the well-established cytoplasmic localization of the prefoldin complex
      (PMID:9630229, PMID:32699605).
    action: ACCEPT
    reason: >-
      Cytoplasm is the primary site of prefoldin chaperone activity. This IEA
      annotation is consistent with higher-confidence IBA and TAS annotations to
      the same term.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0006457 "protein folding" was inferred electronically from InterPro domain
      mapping (IPR016655, the PFD3/prefoldin subunit 3 domain). This IEA annotation is
      consistent with IDA and NAS annotations to the same term, and with the
      well-established role of the prefoldin complex in protein folding (PMID:9630229,
      PMID:30955883).
    action: ACCEPT
    reason: >-
      The IEA annotation to protein folding via InterPro is correct and consistent
      with higher-confidence IDA and NAS annotations. The PFD3 domain (IPR016655) is
      specifically associated with the protein folding function of the prefoldin
      complex (PMID:9630229, PMID:30955883).
- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0016272 "prefoldin complex" was inferred electronically from InterPro domain
      mapping (IPR016655, the PFD3 domain). VBP1 (PFDN3) is one of the two alpha
      subunits of the heterohexameric prefoldin complex (PMID:9630229, PMID:32699605).
      This IEA annotation is consistent with IBA and IDA annotations to the same
      term from PMID:30955883 and PMID:23614719.
    action: ACCEPT
    reason: >-
      VBP1 is a core structural subunit of the prefoldin complex. The IEA mapping
      from the PFD3 domain (IPR016655) to prefoldin complex membership is appropriate
      and consistent with experimental evidence (PMID:9630229, PMID:30955883).
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      GO:0032991 "protein-containing complex" was inferred electronically by the
      ARBA machine learning model (ARBA:ARBA00028902). While technically correct --
      VBP1 is part of the prefoldin complex, which is a protein-containing complex --
      this annotation is redundant and overly general given the more specific
      GO:0016272 "prefoldin complex" annotation that is already present from IBA,
      IEA, and IDA evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an overly general annotation. VBP1 is part of the prefoldin complex
      (GO:0016272), which is a child term of protein-containing complex. The more
      specific term is already annotated with IBA, IEA, and IDA evidence. The generic
      "protein-containing complex" adds no useful information.
# ============================================================
# IPI protein binding annotations
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17698809
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:P35963/HIV-1 gag-pol polyprotein)
      from an IntAct interaction study (PMID:17698809). This interaction between VBP1
      and the HIV-1 gag-pol polyprotein was detected in a protein interaction screen.
      While viral proteins may interact with prefoldin subunits (consistent with the
      known nuclear role of prefoldin in HIV integrase ubiquitination), "protein binding"
      is an uninformative GO term that does not describe any specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The interaction with HIV-1 gag-pol is from
      a high-throughput screen and the term provides no functional insight. The core
      molecular function of VBP1 is better captured by GO:0044183 "protein folding
      chaperone."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22190034
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9Q2G4/viral ORF) from Jager
      et al. 2012 (PMID:22190034), a study mapping the global landscape of HIV-human
      protein complexes. The interaction between VBP1 and a viral protein was identified
      in this high-throughput study. "Protein binding" is an uninformative GO term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. This high-throughput HIV-host interactome
      screen detection does not provide functional insight for VBP1. The core
      molecular function is already captured by more specific terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q8ND90/PNMA1, Q96S82/UBL7,
      Q9NQP4/PFDN4) from Rolland et al. 2014 (PMID:25416956), a proteome-scale map
      of the human interactome network. The interaction with PFDN4 reflects
      intra-complex interactions expected for prefoldin subunits. The interactions with
      PNMA1 and UBL7 are from a large-scale Y2H screen. "Protein binding" is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The VBP1-PFDN4 interaction reflects
      co-membership in the prefoldin complex (already captured by GO:0016272). The
      other interactions are from high-throughput screens and do not provide
      functional insight.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q96S82/UBL7, Q99471/PFDN5,
      Q9NQP4/PFDN4, Q9UHV9/PFDN2) from Huttlin et al. 2017 (PMID:28514442), the
      BioPlex human interactome study. The interactions with PFDN2, PFDN4, and PFDN5
      are expected intra-complex interactions since all are subunits of the prefoldin
      hexamer. The UBL7 interaction is from a large-scale screen. "Protein binding"
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The interactions with PFDN2, PFDN4, and
      PFDN5 reflect co-membership in the prefoldin complex, already captured by
      GO:0016272. High-throughput interactome data does not add functional insight
      beyond complex membership.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with many partners including PFDN2, PFDN4,
      PFDN5, and numerous other proteins) from Luck et al. 2020 (PMID:32296183), a
      reference map of the human binary protein interactome (HuRI). This study
      detected numerous interactions for VBP1 in a large-scale Y2H screen. The
      prefoldin subunit interactions are expected. The many other interactions (with
      transcription factors, kinases, etc.) may reflect the broad substrate
      recognition capacity of prefoldin or may be false positives in a high-throughput
      screen. "Protein binding" is uninformative in all cases.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. This is a large-scale interactome study
      with many detected partners. The prefoldin subunit interactions are already
      captured by GO:0016272. The non-prefoldin interactions do not provide functional
      insight and the generic GO term adds no value.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with multiple partners including PFDN2 and
      various other proteins) from Metzger et al. 2020 (PMID:32814053), an
      interactome mapping study of neurodegenerative disease proteins. The interaction
      with PFDN2 is expected as both are prefoldin subunits. The other interactions
      are from a high-throughput screen focused on neurodegeneration-related proteins.
      "Protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The PFDN2 interaction reflects prefoldin
      complex membership (GO:0016272). The other high-throughput interactions do not
      provide functional insight. The core molecular function is already captured
      by more specific terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q96S82/UBL7, Q99471/PFDN5,
      Q9NQP4/PFDN4, Q9UHV9/PFDN2) from Huttlin et al. 2021 (PMID:33961781), a dual
      proteome-scale network study. This confirms previously observed interactions:
      the intra-prefoldin subunit interactions (PFDN2, PFDN4, PFDN5) and UBL7.
      "Protein binding" remains uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. These are replications of previously
      observed interactions (intra-prefoldin complex; UBL7) that do not add functional
      insight beyond what is captured by GO:0016272 (prefoldin complex).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9NQP4/PFDN4 and
      Q9UHV9/PFDN2) from multimodal cell maps study (PMID:40205054). This is yet
      another replication of VBP1-PFDN2 and VBP1-PFDN4 intra-complex interactions.
      "Protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. This is a further replication of known
      intra-prefoldin complex interactions from a large-scale study. The relevant
      functions are already captured by GO:0016272 (prefoldin complex).
# ============================================================
# IDA annotations (direct experimental)
# ============================================================
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      GO:0005829 "cytosol" was annotated by the Human Protein Atlas (HPA) based on
      curation of immunofluorescence data (GO_REF:0000052). The prefoldin complex
      operates primarily in the cytosol to capture unfolded nascent polypeptides and
      deliver them to TRiC/CCT (PMID:9630229). This is a more specific subcellular
      localization than "cytoplasm" (GO:0005737) and is consistent with the known
      biology. Cytosol is a child of cytoplasm.
    action: ACCEPT
    reason: >-
      Cytosol localization is well-supported by the known biology of the prefoldin
      complex operating in the cytosol to deliver substrates to TRiC/CCT. The HPA
      immunofluorescence data provides direct evidence. This is a more specific and
      informative term than the broader "cytoplasm" annotation.
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers
        target proteins to it.
# ============================================================
# NAS annotations (non-traceable author statement)
# ============================================================
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:32699605
  review:
    summary: >-
      GO:0006457 "protein folding" (NAS) from ComplexPortal, citing Liang et al.
      2020 (PMID:32699605), a comprehensive review of prefoldin complex functions.
      The review describes how "the prefoldin complex helps protein fold correctly
      and prevents aggregation by providing class II chaperones ... with a linear,
      unnatural substrate in the cytoplasm." This NAS annotation is consistent with
      IBA and IDA annotations to the same term and is well-supported.
    action: ACCEPT
    reason: >-
      Protein folding is the core biological process for VBP1. This NAS annotation
      from ComplexPortal cites a well-sourced review (PMID:32699605) that accurately
      describes the protein folding function of the prefoldin complex. Consistent
      with IDA evidence from PMID:30955883.
    supported_by:
    - reference_id: PMID:32699605
      supporting_text: >-
        The prefoldin complex helps protein fold correctly and prevents aggregation
        by providing class II chaperones (Hsp60 molecular chaperones found in
        archaebacteria and eukaryotic cytoplasm) with a linear, unnatural substrate
        in the cytoplasm [2]
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:34761191
  review:
    summary: >-
      GO:0006457 "protein folding" (NAS) from ComplexPortal, citing Herranz-Montoya
      et al. 2021 (PMID:34761191), a comprehensive analysis of prefoldins and their
      implication in cancer. The review describes prefoldins as "evolutionary conserved
      co-chaperones" that "act as co-chaperones escorting misfolded or non-native
      proteins to group II chaperonins." This NAS annotation is consistent with IDA
      and IBA annotations to the same term.
    action: ACCEPT
    reason: >-
      Protein folding is the core biological process for VBP1. This NAS annotation
      from ComplexPortal cites a comprehensive review (PMID:34761191) that accurately
      describes the co-chaperone function of prefoldin subunits. Consistent with
      IDA evidence from PMID:30955883.
    supported_by:
    - reference_id: PMID:34761191
      supporting_text: >-
        PFDNs are prevalently organized into hetero-hexameric complexes. Although
        they have been overlooked since their discovery and their functions remain
        elusive, several reports indicate they act as co-chaperones escorting
        misfolded or non-native proteins to group II chaperonins.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: NAS
  original_reference_id: PMID:34761191
  review:
    summary: >-
      GO:0050821 "protein stabilization" (NAS) from ComplexPortal, citing
      Herranz-Montoya et al. 2021 (PMID:34761191). The GO definition of protein
      stabilization is "Any process involved in maintaining the structure and
      integrity of a protein and preventing it from degradation or aggregation."
      Prefoldin does prevent aggregation of unfolded substrates by capturing them
      and delivering them to TRiC/CCT (PMID:9630229). For VBP1 specifically, there
      is additional evidence that prefoldin/VBP1 prevents pVHL aggregation and
      supports its maturation (deep research: Le Goff et al. 2016, Tahmaz et al.
      2022). However, "protein stabilization" typically implies maintaining a folded
      protein in its native state, whereas prefoldin acts primarily on unfolded
      nascent polypeptides as a holdase. The term is not entirely wrong but
      mischaracterizes the primary chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      While prefoldin does prevent protein aggregation (which is part of the GO
      definition of protein stabilization), and VBP1/prefoldin specifically helps
      prevent pVHL aggregation, the primary function is to capture unfolded substrates
      and transfer them to TRiC/CCT for folding. "Protein stabilization" represents
      a secondary aspect rather than the core activity. The core process (protein
      folding, GO:0006457) is already well-annotated.
    supported_by:
    - reference_id: PMID:34761191
      supporting_text: >-
        PFDNs are prevalently organized into hetero-hexameric complexes. Although
        they have been overlooked since their discovery and their functions remain
        elusive, several reports indicate they act as co-chaperones escorting
        misfolded or non-native proteins to group II chaperonins.
# ============================================================
# IDA annotations from PMID:30955883 (Gestaut et al. 2019)
# ============================================================
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      GO:0006457 "protein folding" (IDA) from Gestaut et al. 2019 (PMID:30955883),
      which used cryo-EM, crosslinking mass spectrometry, and biochemical
      reconstitution to characterize the structural and functional interplay between
      the prefoldin (PFD) complex and TRiC/CCT chaperonin. The study demonstrates
      that "PFD can act after TRiC bound its substrates to enhance the rate and yield
      of the folding reaction, suppressing non-productive reaction cycles," directly
      showing involvement in protein folding. This is the highest-quality direct
      experimental evidence for the protein folding function of the prefoldin complex
      including VBP1.
    action: ACCEPT
    reason: >-
      This IDA annotation is supported by strong direct experimental evidence from
      Gestaut et al. 2019 (PMID:30955883), which demonstrated through cryo-EM and
      biochemical approaches that the PFD-TRiC supra-chaperone assembly enhances
      protein folding rates. Protein folding is the core biological process for VBP1.
    supported_by:
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
    - reference_id: PMID:30955883
      supporting_text: >-
        The supra-chaperone assembly formed by PFD and TRiC is essential to
        prevent toxic conformations and ensure effective cellular proteostasis.
- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      GO:0016272 "prefoldin complex" (IDA) from Gestaut et al. 2019 (PMID:30955883).
      This study used reconstituted human prefoldin complex containing all six
      subunits including VBP1/PFDN3 and characterized its structure through cryo-EM
      and crosslinking mass spectrometry. The study resolved the architecture of the
      PFD-TRiC supra-chaperone complex, directly demonstrating that VBP1 is a
      component of the prefoldin complex. The cryo-EM structures (PDB: 6NR8, 6NR9,
      6NRB, 6NRC, 6NRD) include VBP1 as chain 3.
    action: ACCEPT
    reason: >-
      VBP1 is a core structural alpha subunit of the prefoldin complex. This IDA
      annotation is supported by high-resolution cryo-EM structural data from
      Gestaut et al. 2019 (PMID:30955883) that directly demonstrates VBP1 as a
      component of the human prefoldin complex.
    supported_by:
    - reference_id: PMID:30955883
      supporting_text: >-
        Maintaining proteostasis in eukaryotic protein folding involves cooperation
        of distinct chaperone systems. To understand how the essential ring-shaped
        chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we
        integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry
        and biochemical and cellular approaches to elucidate the structural and
        functional interplay between TRiC/CCT and PFD.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      GO:0051082 "unfolded protein binding" is being obsoleted (go-ontology#30962).
      This IDA annotation cites Gestaut et al. 2019 (PMID:30955883), which
      demonstrated that prefoldin associates with TRiC through a conserved
      electrostatic interface and undergoes conformational cycling between "latched"
      (open) and "engaged" (closed) states during substrate transfer. The paper shows
      that PFD functions not merely as a passive binder of unfolded substrates but
      as an active co-chaperone that enhances folding rates. GO:0044183 "protein
      folding chaperone" (defined as "Binding to a protein or a protein-containing
      complex to assist the protein folding process") is the appropriate replacement,
      capturing the functional holdase/transfer chaperone role.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. Gestaut et al. 2019 (PMID:30955883) demonstrates
      that prefoldin functions as a co-chaperone/holdase that cooperates with TRiC/CCT
      in substrate folding, not merely as an unfolded protein binder. GO:0044183
      "protein folding chaperone" accurately describes the co-chaperone activity of
      VBP1 as part of the prefoldin complex.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:9630229
    supported_by:
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
    - reference_id: PMID:30955883
      supporting_text: >-
        Disrupting the TRiC-PFD interaction in vivo is strongly deleterious,
        leading to accumulation of amyloid aggregates.
    - reference_id: PMID:9630229
      supporting_text: >-
        Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers
        target proteins to it. ... prefoldin promotes folding in an environment in
        which there are many competing pathways for nonnative proteins.
# ============================================================
# IDA annotations from PMID:23614719 (Sorgjerd et al. 2013)
# ============================================================
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      GO:0001540 "amyloid-beta binding" (IDA) from Sorgjerd et al. 2013
      (PMID:23614719). This study demonstrated that recombinant human prefoldin
      (hPFD) inhibits amyloid-beta (Abeta 1-42) fibrillation in vitro and induces
      formation of soluble Abeta oligomers with reduced toxicity. Thioflavin T
      measurements and immunoblotting showed that hPFD directly interacts with Abeta
      peptides. While this demonstrates that the prefoldin complex can bind Abeta,
      this is not the core function of VBP1 -- it reflects the general
      chaperone/holdase property of prefoldin applied to an amyloidogenic substrate.
      The annotation was made on the intact prefoldin complex, not VBP1 individually.
    action: KEEP_AS_NON_CORE
    reason: >-
      Amyloid-beta binding is a secondary, non-core function that reflects the
      general holdase/chaperone activity of the prefoldin complex applied to an
      amyloidogenic substrate. The study (PMID:23614719) used the intact hexameric
      complex rather than individual VBP1. While the data are solid, this represents
      a peripheral function compared to the core role in actin/tubulin folding via
      TRiC/CCT delivery.
    supported_by:
    - reference_id: PMID:23614719
      supporting_text: >-
        we investigated the effect of recombinant human PFD (hPFD) on Abeta(1-42)
        aggregation in vitro and found that hPFD inhibited Abeta fibrillation and
        induced formation of soluble Abeta oligomers.
- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      GO:0016272 "prefoldin complex" (IDA) from Sorgjerd et al. 2013 (PMID:23614719).
      This study expressed and purified recombinant human prefoldin complex (hPFD)
      containing all six subunits including VBP1/PFDN3 to investigate its effect on
      amyloid-beta aggregation. The successful reconstitution and purification of the
      hexameric complex provides direct evidence for VBP1 membership in the prefoldin
      complex. Consistent with IDA from PMID:30955883 and IBA/IEA annotations.
    action: ACCEPT
    reason: >-
      VBP1 is a core structural alpha subunit of the prefoldin complex. This IDA
      annotation from PMID:23614719 provides independent experimental evidence
      through reconstitution of the human prefoldin hexamer, consistent with the
      structural data from PMID:30955883.
    supported_by:
    - reference_id: PMID:23614719
      supporting_text: >-
        Prefoldin (PFD) is a molecular chaperone that prevents aggregation of
        misfolded proteins.
- term:
    id: GO:1905907
    label: negative regulation of amyloid fibril formation
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      GO:1905907 "negative regulation of amyloid fibril formation" (IDA) from
      Sorgjerd et al. 2013 (PMID:23614719). The study demonstrated that recombinant
      human prefoldin "inhibited Abeta fibrillation and induced formation of soluble
      Abeta oligomers" that were 30-40% less toxic than Abeta fibrils. Thioflavin T
      measurements confirmed reduced fibril formation. While the experimental evidence
      is sound, this represents a non-core function of the prefoldin complex -- an
      extension of its general holdase/chaperone properties to amyloidogenic substrates.
      The study was performed on the intact hexameric complex, not VBP1 individually.
    action: KEEP_AS_NON_CORE
    reason: >-
      The experimental evidence from PMID:23614719 is solid, but this is a secondary
      function reflecting the general anti-aggregation properties of the prefoldin
      complex rather than its core role in delivering unfolded actin/tubulin to
      TRiC/CCT. The study was performed in vitro on the intact hexameric complex,
      and the relevance to VBP1 specifically (as opposed to the complex as a whole)
      is indirect.
    supported_by:
    - reference_id: PMID:23614719
      supporting_text: >-
        we investigated the effect of recombinant human PFD (hPFD) on Abeta(1-42)
        aggregation in vitro and found that hPFD inhibited Abeta fibrillation and
        induced formation of soluble Abeta oligomers.
    - reference_id: PMID:23614719
      supporting_text: >-
        Our findings show a relation between cytotoxicity of Abeta oligomers and
        structure and suggest a possible protective role of PFD in AD.
# ============================================================
# TAS annotation
# ============================================================
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:8674032
  review:
    summary: >-
      GO:0005737 "cytoplasm" (TAS) from Tsuchiya et al. 1996 (PMID:8674032), the
      original paper that identified VBP1 as a protein binding to the VHL tumor
      suppressor. This study characterized VBP1 and showed its cytoplasmic localization,
      with the note that in complex with VHL it can translocate to the nucleus. This
      is the foundational localization study for VBP1 and is consistent with the IBA
      and IEA annotations to the same term.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization of VBP1 is well-established from the original
      discovery paper (PMID:8674032) and is consistent with the known biology of
      the prefoldin complex operating in the cytoplasm (PMID:9630229). This TAS
      annotation is appropriate and well-supported.
# ============================================================
# NEW annotations (missing from current set)
# ============================================================
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      GO:0044183 "protein folding chaperone" is the most appropriate molecular
      function term for VBP1. Unlike PFDN1, VBP1 lacks an IBA annotation to this
      term. Gestaut et al. 2019 (PMID:30955883) demonstrated through cryo-EM and
      biochemical reconstitution that the prefoldin complex (containing VBP1) functions
      as a co-chaperone that delivers unfolded substrates to TRiC/CCT and enhances
      the rate and yield of folding. Vainberg et al. 1998 (PMID:9630229) originally
      characterized prefoldin as "a chaperone that delivers unfolded proteins to
      cytosolic chaperonin." The GO:0044183 definition ("Binding to a protein or a
      protein-containing complex to assist the protein folding process") precisely
      captures the holdase/transfer chaperone function of VBP1 within the prefoldin
      complex. This is also the recommended replacement for the obsoleting GO:0051082.
    action: NEW
    reason: >-
      GO:0044183 "protein folding chaperone" is the core molecular function of VBP1
      as part of the prefoldin complex. This term is missing from the current
      annotation set (unlike PFDN1 which has it via IBA). The evidence from
      PMID:30955883 and PMID:9630229 directly supports this annotation. This is
      also the recommended replacement for GO:0051082 "unfolded protein binding"
      which is being obsoleted.
    additional_reference_ids:
    - PMID:9630229
    supported_by:
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
    - reference_id: PMID:9630229
      supporting_text: >-
        We describe the discovery of a heterohexameric chaperone protein, prefoldin,
        based on its ability to capture unfolded actin. Prefoldin binds specifically
        to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
core_functions:
- description: >-
    VBP1 (PFDN3) is an alpha-type subunit of the heterohexameric prefoldin co-chaperone
    complex that captures unfolded nascent polypeptides (primarily actin and tubulin) and
    delivers them to the TRiC/CCT chaperonin for ATP-dependent folding. As one of the two
    alpha subunits (with PFDN5), VBP1 forms the longer coiled-coil tentacles of the
    jellyfish-shaped prefoldin architecture. Cryo-EM structural data show VBP1 as chain 3
    in the PFD-TRiC supra-chaperone complex. The prefoldin-TRiC interaction enhances
    protein folding rates and suppresses non-productive reaction cycles. Disrupting this
    interaction in vivo leads to accumulation of toxic amyloid aggregates.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
    - id: GO:0006457
      label: protein folding
    - id: GO:0007021
      label: tubulin complex assembly
    - id: GO:0007017
      label: microtubule-based process
  locations:
    - id: GO:0005829
      label: cytosol
  in_complex:
    id: GO:0016272
    label: prefoldin complex
  supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        We describe the discovery of a heterohexameric chaperone protein, prefoldin,
        based on its ability to capture unfolded actin. Prefoldin binds specifically
        to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
    - reference_id: PMID:9630229
      supporting_text: >-
        Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results in
        a phenotype similar to those found when c-cpn is mutated, namely impaired
        functions of the actin and tubulin-based cytoskeleton.
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: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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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:8674032
  title: Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau
    (VHL) tumor suppressor gene product.
  findings: []
- id: PMID:9630229
  title: Prefoldin, a chaperone that delivers unfolded proteins to cytosolic chaperonin.
  findings: []
- id: PMID:17698809
  title: von Hippel Lindau binding protein 1-mediated degradation of integrase affects
    HIV-1 gene expression at a postintegration step.
  findings: []
- id: PMID:22190034
  title: Global landscape of HIV-human protein complexes.
  findings: []
- id: PMID:23614719
  title: "Human prefoldin inhibits amyloid-\u03B2 (A\u03B2) fibrillation and contributes\
    \ to formation of nontoxic A\u03B2 aggregates."
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:30955883
  title: The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic
    Interface Essential for Cellular Proteostasis.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32699605
  title: The functions and mechanisms of prefoldin complex and prefoldin-subunits.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34761191
  title: A comprehensive analysis of prefoldins and their implication in cancer.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []