CPR6

id: P53691
gene_symbol: CPR6
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  CPR6 is one of two CyP-40-like cyclophilin immunophilins in S. cerevisiae (the other being CPR7).
  It is a peptidyl-prolyl cis-trans isomerase (PPIase, EC 5.2.1.8) that functions as an Hsp90
  co-chaperone. CPR6 contains an N-terminal cyclophilin PPIase domain and a C-terminal TPR
  (tetratricopeptide repeat) domain that mediates binding to Hsp90 (HSP82/HSC82). It catalyzes the
  cis-trans isomerization of proline imidic peptide bonds in oligopeptides and contributes to
  protein refolding. CPR6 binds cyclosporin A. Unlike CPR7, CPR6 is not essential for normal growth.
  CPR6 interacts with Hsp90 and also associates with ribosomes.
existing_annotations:
# ============================================================================
# IBA ANNOTATIONS
# ============================================================================
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CPR6 is a cyclophilin with well-established PPIase activity. IBA annotation is correct.
    action: ACCEPT
    reason: >-
      PPIase activity is the core molecular function of CPR6. UniProt describes it as catalyzing
      cis-trans isomerization of proline imidic peptide bonds (EC 5.2.1.8). IDA evidence from
      PMID:10942767 and PMID:9191025 confirms this activity.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CPR6 is a cytoplasmic protein. IBA annotation is correct.
    action: ACCEPT
    reason: >-
      Consistent with IDA evidence (PMID:9191025) and HDA evidence (PMID:11914276, PMID:14562095)
      for cytoplasmic localization.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CPR6 contributes to protein folding through its PPIase activity and co-chaperone function with Hsp90.
    action: ACCEPT
    reason: >-
      CPR6 participates in protein folding through two mechanisms: its PPIase catalytic activity
      (proline isomerization facilitates protein folding) and its role as an Hsp90 co-chaperone
      via its TPR domain. IDA and IPI evidence from PMID:9927435 supports this annotation.
- term:
    id: GO:0016018
    label: cyclosporin A binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CPR6 is a cyclophilin that binds cyclosporin A. IBA annotation is correct.
    action: ACCEPT
    reason: >-
      Cyclosporin A binding is a defining characteristic of cyclophilins. The name CPR6
      (Cyclosporin-sensitive Proline Rotamase 6) reflects this property. The IBA inference
      is well-supported phylogenetically.
# ============================================================================
# IEA ANNOTATIONS
# ============================================================================
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for PPIase activity. Redundant with IBA and IDA but correct.
    action: ACCEPT
    reason: >-
      Consistent with IBA and IDA annotations for PPIase activity.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for cytoplasm from UniProt subcellular location mapping. Correct.
    action: ACCEPT
    reason: >-
      Consistent with IDA and HDA evidence for cytoplasmic localization.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for protein folding from InterPro. Correct.
    action: ACCEPT
    reason: >-
      Consistent with IBA and experimental annotations for protein folding involvement.
- term:
    id: GO:0016853
    label: isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping. Broader than PPIase activity but not incorrect.
    action: ACCEPT
    reason: >-
      Isomerase activity is a parent term of peptidyl-prolyl cis-trans isomerase activity. While
      more specific annotations exist, this broader IEA annotation is not incorrect.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA prediction for protein refolding. Supported by IDA evidence.
    action: ACCEPT
    reason: >-
      Supported by IDA evidence from PMID:10942767 which showed CPR6 has protein refolding activity.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA prediction for unfolded protein binding. GO:0051082 is proposed for obsoletion.
      CPR6 is a PPIase co-chaperone, not an independent chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0051082 is proposed for obsoletion. CPR6 is primarily a PPIase that functions as an
      Hsp90 co-chaperone. While it can bind unfolded proteins in in vitro assays (PMID:10942767),
      its primary mechanism of action is proline isomerization, not independent unfolded protein
      binding. The IDA from PMID:10942767 showed chaperone-like activity in refolding assays, but
      this is secondary to its PPIase function. The core MF is GO:0003755 (PPIase activity).
# ============================================================================
# IPI PROTEIN BINDING ANNOTATIONS
# ============================================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11805837
  review:
    summary: >-
      IPI from mass spectrometry study. Uninformative "protein binding" annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. CPR6 interacts with Hsp90 via its TPR domain;
      the more informative annotation would be GO:0051087 (protein-folding chaperone binding).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15766533
  review:
    summary: >-
      IPI from chaperone network study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for an Hsp90 co-chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554755
  review:
    summary: >-
      IPI from large-scale protein complex study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for an Hsp90 co-chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19536198
  review:
    summary: >-
      IPI from atlas of chaperone-protein interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for an Hsp90 co-chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21170051
  review:
    summary: >-
      IPI from mixed Hsp90-cochaperone complex study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for an Hsp90 co-chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23396352
  review:
    summary: >-
      IPI from Aha1 integration into Hsp90 co-chaperone cycle study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for an Hsp90 co-chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37968396
  review:
    summary: >-
      IPI from yeast protein interactome architecture study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for an Hsp90 co-chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8873448
  review:
    summary: >-
      IPI from original identification of CPR6 as CyP-40-like cyclophilin.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for an Hsp90 co-chaperone.
# ============================================================================
# OTHER EXPERIMENTAL ANNOTATIONS
# ============================================================================
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:11914276
  review:
    summary: >-
      High-throughput data for cytoplasmic localization.
    action: ACCEPT
    reason: >-
      Consistent with IDA evidence. Core localization.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:14562095
  review:
    summary: >-
      High-throughput GFP localization data confirming cytoplasm.
    action: ACCEPT
    reason: >-
      Global protein localization study. Consistent with IDA evidence.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IPI
  original_reference_id: PMID:9927435
  review:
    summary: >-
      IPI evidence for protein folding involvement through interaction with Hsp90.
    action: ACCEPT
    reason: >-
      CPR6 participates in protein folding as an Hsp90 co-chaperone. The IPI evidence documents
      the functional interaction in the context of protein folding.
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IDA
  original_reference_id: PMID:25380751
  review:
    summary: >-
      IDA evidence for ribosome binding. CPR6 associates with ribosomes.
    action: KEEP_AS_NON_CORE
    reason: >-
      CPR6 has been shown to bind ribosomes by direct assay. This may be related to co-translational
      protein folding but is not the core PPIase/co-chaperone function.
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:10942767
  review:
    summary: >-
      IDA evidence for PPIase activity from comparative study of CPR6 and CPR7.
    action: ACCEPT
    reason: >-
      Direct assay demonstrates PPIase activity. Study compared CPR6 and CPR7, showing both
      have PPIase activity but differ in other functional properties.
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:9191025
  review:
    summary: >-
      IDA evidence for PPIase activity from functional analysis of yeast 40 kDa cyclophilin.
    action: ACCEPT
    reason: >-
      Direct assay demonstrates PPIase activity. Core molecular function of CPR6.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9191025
  review:
    summary: >-
      IDA evidence for cytoplasmic localization.
    action: ACCEPT
    reason: >-
      Core localization of CPR6.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:9927435
  review:
    summary: >-
      IDA evidence for protein folding involvement.
    action: ACCEPT
    reason: >-
      Direct assay demonstrates CPR6 role in protein folding, consistent with its PPIase
      and co-chaperone functions.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IDA
  original_reference_id: PMID:10942767
  review:
    summary: >-
      IDA evidence for protein refolding activity from comparative study of CPR6 and CPR7.
    action: ACCEPT
    reason: >-
      PMID:10942767 demonstrated that CPR6 has protein refolding activity in vitro.
      This is consistent with its PPIase and co-chaperone functions.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:10942767
  review:
    summary: >-
      IDA evidence for unfolded protein binding. GO:0051082 is proposed for obsoletion.
      CPR6 is primarily a PPIase, not an independent chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0051082 is proposed for obsoletion. While PMID:10942767 showed CPR6 can bind
      unfolded proteins in vitro, its primary mechanism is proline isomerization (GO:0003755)
      and its co-chaperone function with Hsp90. The unfolded protein binding observed in vitro
      is secondary to these core functions. Marking as over-annotated rather than MODIFY because
      CPR6 is not an ATP-dependent chaperone and GO:0044183 would not be appropriate.
core_functions:
- description: >-
    Primary molecular function: peptidyl-prolyl cis-trans isomerase (PPIase) activity.
    CPR6 catalyzes the cis-trans isomerization of proline imidic peptide bonds (EC 5.2.1.8).
    Supported by IBA, IDA (PMID:10942767, PMID:9191025), and IEA evidence.
  molecular_function:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  locations:
  - id: GO:0005737
    label: cytoplasm
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:10942767
  title: Cpr6 and Cpr7, two closely related Hsp90-associated immunophilins from Saccharomyces
    cerevisiae, differ in their functional properties.
  findings:
  - statement: CPR6 has PPIase activity and protein refolding activity in vitro
  - statement: CPR6 and CPR7 differ in their functional properties despite structural similarity
- id: PMID:11805837
  title: Systematic identification of protein complexes in Saccharomyces cerevisiae
    by mass spectrometry.
  findings: []
- id: PMID:11914276
  title: Subcellular localization of the yeast proteome.
  findings: []
- id: PMID:14562095
  title: Global analysis of protein localization in budding yeast.
  findings: []
- id: PMID:15766533
  title: 'Navigating the chaperone network: an integrative map of physical and genetic
    interactions mediated by the hsp90 chaperone.'
  findings: []
- id: PMID:16554755
  title: Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
  findings: []
- id: PMID:19536198
  title: 'An atlas of chaperone-protein interactions in Saccharomyces cerevisiae:
    implications to protein folding pathways in the cell.'
  findings: []
- id: PMID:21170051
  title: Mixed Hsp90-cochaperone complexes are important for the progression of the
    reaction cycle.
  findings: []
- id: PMID:23396352
  title: Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle.
  findings: []
- id: PMID:25380751
  title: The Hsp90 cochaperones Cpr6, Cpr7, and Cns1 interact with the intact
    ribosome.
  findings: []
- id: PMID:37968396
  title: The social and structural architecture of the yeast protein interactome.
  findings: []
- id: PMID:8873448
  title: Identification of two CyP-40-like cyclophilins in Saccharomyces cerevisiae,
    one of which is required for normal growth.
  findings: []
- id: PMID:9191025
  title: Functional analysis of the yeast 40 kDa cyclophilin Cyp40 and its role for
    viability and steroid receptor regulation.
  findings:
  - statement: CPR6 has PPIase catalytic activity and localizes to the cytoplasm
- id: PMID:9927435
  title: Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain
    co-chaperones.
  findings:
  - statement: CPR6 participates in protein folding as an Hsp90 co-chaperone