Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: BAG-1 is a soluble co-chaperone that acts on cytoplasmic Hsp70/Hsc70; cytoplasmic localization is expected and consistent with the absence of any transmembrane or signal-peptide features.
GO:0005634 nucleus	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Nuclear localization in the BAG family is a property of the mammalian BAG-1L isoform, which carries an N-terminal extension bearing a nuclear-localization region. The single 210-residue worm protein lacks that extension and there is no experimental evidence for nuclear BAG-1 in C. elegans, so this phylogenetically propagated term likely over-annotates an isoform-specific mammalian feature. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000269156 · BAG family node (nucleus IBA source) SUPPORTS SOURCE BUT NOT TARGET Nuclear localization derives from the N-terminally extended mammalian BAG-1L isoform; the single short worm protein lacks that nuclear-targeting extension, so the source annotation is sound but does not transfer.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosol is a more precise and appropriate location for a soluble BAG-domain nucleotide-exchange factor acting on cytosolic Hsc70; consistent with the lack of membrane or organelle-targeting features.
GO:0016020 membrane	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Worm BAG-1 has no transmembrane segment, no signal peptide, and no lipid-anchor features; it is a soluble cytosolic co-chaperone. The membrane term is a weak phylogenetic propagation (partly from a BAG3-type ortholog) and is not expected to apply to this protein. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000269156 · BAG family node (membrane IBA source) SUPPORTS SOURCE BUT NOT TARGET Membrane association is not expected for a soluble BAG-domain NEF with no transmembrane segment or lipid anchor; the term is partly propagated from a BAG3-type ortholog and does not transfer to this protein.
GO:0000774 adenyl-nucleotide exchange factor activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the defining molecular function of the BAG family: the BAG domain binds the Hsp70/Hsc70 ATPase domain and promotes ADP release / ATP-dependent substrate discharge, i.e. nucleotide exchange. Well supported by family biology and the worm structure, and consistent with the experimental Hsc70 ATPase stimulation measured for worm BAG-1. Supporting Evidence: PMID:15333932 Binding of the BAG domain to the eukaryotic chaperone heat-shock protein (Hsp70) promotes ATP-dependent release of the protein substrate from Hsp70.
GO:0050821 protein stabilization	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Plausible downstream consequence of BAG-1's modulation of the Hsp70/Hsc70 cycle, propagated from mammalian orthologs. No worm-specific evidence that BAG-1 stabilizes particular clients, so retained as a non-core biological process.
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	Summary: Binding to the Hsp70/Hsc70 chaperone via the BAG domain is central to BAG-1 function and is the enabling interaction underlying its nucleotide-exchange activity. Well supported for a BAG-domain protein. Supporting Evidence: PMID:9873016 BAG-1 binds the ATPase domains of Hsp70 and Hsc70, modulating their chaperone activity and functioning as a competitive antagonist of the co-chaperone Hip
GO:0051087 protein-folding chaperone binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation from the BAG-domain signatures. Correctly captures Hsp70/Hsc70 chaperone binding and corroborates the phylogenetic and experimental support for this interaction (an independent evidence line for the same accepted chaperone-binding function).
GO:0005515 protein binding	IPI PMID:14704431 A map of the interactome network of the metazoan C. elegans.	KEEP AS NON CORE	Summary: High-throughput yeast-two-hybrid interaction with the DUF727 protein Y43F8B.2 (Q9XWX7), a partner of unknown function that is not an Hsp70. The generic "protein binding" term is uninformative about BAG-1's molecular function; retained as a real but non-core experimental interaction. Supporting Evidence: PMID:14704431 more than 4000 interactions were identified from high-throughput, yeast two-hybrid (HT=Y2H) screens
GO:0005515 protein binding	IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans...	KEEP AS NON CORE	Summary: Second high-throughput yeast-two-hybrid report of the same Y43F8B.2 (Q9XWX7) interaction. As above, the generic "protein binding" term is uninformative about function; retained as a non-core experimental interaction rather than a core molecular function. Supporting Evidence: PMID:19123269 We present an expanded C. elegans protein-protein interaction network, or 'interactome' map, derived from testing a matrix of approximately 10,000 x approximately 10,000 proteins using a highly specific, high-throughput yeast two-hybrid system.
GO:0001671 ATPase activator activity	IDA PMID:25053410 The balanced regulation of Hsc70 by DNJ-13 and UNC-23 is req...	ACCEPT	Summary: Experimentally supported for worm BAG-1: as a nucleotide-exchange factor it accelerates the Hsc70 ATPase cycle. Papsdorf et al. measured ATPase stimulation and folding regulation for the BAG cofactors and report that BAG-1 acts with higher affinity than the paralog UNC-23. This mechanistically complements the nucleotide-exchange-factor annotation and is a core function. Supporting Evidence: PMID:25053410 C-terminal fragments of UNC-23 instead perform all Hsc70-related functions, like ATPase stimulation and regulation of folding activity, albeit with lower affinity than BAG-1
GO:0006457 protein folding	ISS PMID:9873016 An evolutionarily conserved family of Hsp70/Hsc70 molecular ...	ACCEPT	Summary: As an Hsp70/Hsc70 co-chaperone that regulates the ATP-driven folding cycle, BAG-1 is legitimately involved in the protein-folding process; the involved_in qualifier does not imply it is itself a foldase (indeed excess BAG can inhibit chaperone activity). The specific regulatory mechanism is captured by the nucleotide-exchange-factor and ATPase-activator annotations. Supporting Evidence: PMID:9873016 The human BAG-1, BAG-2, and BAG-3 proteins bind with high affinity (KD congruent with 1-10 nM) to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner
GO:0051087 protein-folding chaperone binding	ISS PMID:15333932 Structural genomics of Caenorhabditis elegans: structure of ...	ACCEPT	Summary: Sequence/structure-based inference of Hsp70 chaperone binding, supported by the crystal structure of the worm BAG domain and its documented role in Hsp70-dependent substrate release. An independent evidence line for the same accepted chaperone-binding function. Supporting Evidence: PMID:15333932 Binding of the BAG domain to the eukaryotic chaperone heat-shock protein (Hsp70) promotes ATP-dependent release of the protein substrate from Hsp70.

Core Functions

BAG-1 is a BAG-domain co-chaperone that acts as a nucleotide-exchange factor (NEF) for cytosolic Hsp70/Hsc70 (worm HSP-1). Its C-terminal BAG domain binds the chaperone's nucleotide-binding (ATPase) domain and promotes ADP release, accelerating the ATP-driven cycle and ATP-dependent discharge of client substrates. Experimentally, worm BAG-1 stimulates the Hsc70 ATPase (with higher affinity than the paralog UNC-23), and thereby tunes chaperone-assisted folding; the same activity can antagonize the chaperone when the cofactor is in excess.

Molecular Function:

adenyl-nucleotide exchange factor activity

Directly Involved In:

protein folding

Cellular Locations:

cytosol

Supporting Evidence:

PMID:15333932
Binding of the BAG domain to the eukaryotic chaperone heat-shock protein (Hsp70) promotes ATP-dependent release of the protein substrate from Hsp70.
PMID:9873016
BAG-1 binds the ATPase domains of Hsp70 and Hsc70, modulating their chaperone activity and functioning as a competitive antagonist of the co-chaperone Hip
PMID:25053410
C-terminal fragments of UNC-23 instead perform all Hsc70-related functions, like ATPase stimulation and regulation of folding activity, albeit with lower affinity than BAG-1

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

PMID:9873016

An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.

PMID:15333932

Structural genomics of Caenorhabditis elegans: structure of the BAG domain.

PMID:19123269

Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.

PMID:25053410

The balanced regulation of Hsc70 by DNJ-13 and UNC-23 is required for muscle functionality.

PMID:14704431

A map of the interactome network of the metazoan C. elegans.

file:worm/bag-1/bag-1-notes.md

Reviewer notes for C. elegans bag-1

Suggested Experiments

Experiment: Generate and phenotype a bag-1 loss-of-function allele (CRISPR deletion or RNAi), alone and combined with unc-23 loss, assaying viability, motility, thermotolerance, and aggregation/proteostasis reporters to test whether bag-1 has an independent role or is redundant with unc-23.

Experiment: Affinity-purify tagged BAG-1 from worm lysates followed by mass spectrometry to define the native BAG-1 interactome (HSP-1/Hsc70 and clients), and combine with in-vitro Hsc70 ATPase and luciferase refolding assays to quantify BAG-1's effect on the chaperone cycle.

Knowledge Gaps

What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).

Gap: No in-vivo client or substrate of C. elegans BAG-1 has been identified, and it is untested whether worm BAG-1 biases Hsc70-bound clients toward productive refolding or, via its ubiquitin-like domain, toward proteasomal degradation (the folding-versus-degradation decision that mammalian BAG-1 helps make).

OPEN BIOLOGY BP_DARK

What is known: It is firmly established that BAG-1 is a BAG-domain nucleotide-exchange factor that binds the Hsp70/Hsc70 ATPase domain, stimulates the Hsc70 ATPase, and promotes ATP-dependent substrate release, and that it carries an N-terminal ubiquitin-like domain. What clients pass through this activity in the worm, and what fate BAG-1 directs them to, are unknown.

Significance: The functional output of an Hsp70 NEF depends entirely on which clients it engages and whether it promotes their folding or clearance; without this, the worm-specific biological role of BAG-1 cannot be assigned, and its relationship to proteostasis-network aging phenotypes remains inferential.

What would resolve it: Affinity-proteomics / co-immunoprecipitation of BAG-1 (and BAG-1-vs-UNC-23) from C. elegans to define native clients, combined with degradation/refolding reporter assays and tests of the ubiquitin-like-domain proteasome link, would close the gap.

Provenance (the field's own admissions):

"The mechanisms by which Hsp70 family chaperones are regulated, however, are only partly understood." — PMID:9873016
"No in-vivo client or substrate has been identified for C. elegans BAG-1, and it is untested whether worm BAG-1 channels Hsc70 clients toward productive refolding or toward proteasomal degradation." — file:worm/bag-1/bag-1-notes.md

Gap: No loss-of-function phenotype has been reported for the bag-1 gene itself in C. elegans, so it is unknown whether bag-1 is essential, is functionally redundant with its paralog unc-23, or has a distinct tissue-restricted role.

OPEN BIOLOGY BP_DARK

What is known: In this cofactor system the characterized in-vivo phenotype (severe motility dysfunction, muscle-attachment-site localization) belongs to the paralog UNC-23/BAG2, whereas BAG-1 has only been characterized biochemically (higher Hsc70 affinity than UNC-23). A bag-1 mutant or RNAi phenotype is not described in the cached literature.

Significance: Whether bag-1 is dispensable, buffered by unc-23, or independently required in a particular tissue determines its true biological role and its weight in the worm proteostasis network.

What would resolve it: Characterization of a bag-1 deletion/RNAi (alone and in a unc-23 background) for viability, motility, stress resistance, and proteostasis reporters would define the biological role and test redundancy with unc-23.

Provenance (the field's own admissions):

"one of them being UNC-23, whose mutation induces severe motility dysfunctions" — PMID:25053410
"No loss-of-function phenotype has been reported for the bag-1 gene itself in C. elegans, so it is unknown whether bag-1 is essential, redundant with the paralog unc-23, or has a tissue-restricted role." — file:worm/bag-1/bag-1-notes.md

Gap: A direct physical BAG-1-to-HSP-1/Hsc70 complex in C. elegans has not been demonstrated, and the subcellular site of BAG-1 action in the worm is untested; the only experimentally reported worm partner is the DUF727 protein Y43F8B.2, whose functional relationship to BAG-1 is unexplained.

OPEN BIOLOGYCURATION CC_DARK

What is known: Family biology and the worm BAG-domain crystal structure predict binding to the Hsp70/Hsc70 ATPase domain, and biochemistry shows worm BAG-1 stimulates Hsc70; but the demonstrated worm two-hybrid partner is Y43F8B.2, not HSP-1, and no localization data exist for endogenous BAG-1.

Significance: Establishing the physiological BAG-1/Hsc70 complex and where it forms would convert the inferred co-chaperone role into a directly evidenced one and clarify the meaning (if any) of the Y43F8B.2 interaction.

What would resolve it: Co-immunoprecipitation or proximity labeling of endogenous BAG-1 with HSP-1, plus a tagged-BAG-1 expression/localization reporter, would confirm the complex and its site of action.

Provenance (the field's own admissions):

"The structure may represent a new folding type of the BAG domain." — PMID:15333932
"The only experimentally demonstrated physical partner of worm BAG-1 is the DUF727 protein Y43F8B.2, and a direct BAG-1 to HSP-1/Hsc70 complex in C. elegans has not been shown; the subcellular site of BAG-1 action in the worm is untested." — file:worm/bag-1/bag-1-notes.md

📚 Additional Documentation

Notes

(bag-1-notes.md)

bag-1 (C. elegans) research notes

UniProt: O44739 (BAG1_CAEEL), "BAG family molecular chaperone regulator 1".
Gene: bag-1; ORF F57B10.11; WormBase WBGene00000236; Chromosome I. 210 aa, 24 kDa.
NCBITaxon:6239.

Identity check

Confirmed the record is the BAG-domain Hsp70/Hsc70 co-chaperone (nucleotide-exchange
factor), not a mis-named gene. UniProt DE = "BAG family molecular chaperone regulator 1";
domains: a ubiquitin-like domain (8–85) and a BAG domain (108–194); PDB 1T7S
(BAG domain, residues 74–210). Family founder for the C. elegans BAG proteins together
with UNC-23 (BAG2 ortholog).

Domain architecture / structure

Ubiquitin-like (UBL) domain FT 8–85 (PROSITE PRU00214); BAG domain FT 108–194
(PROSITE PRU00369). Pfam PF02179 (BAG) + PF00240 (ubiquitin). InterPro IPR017093
(BAG-1), IPR003103/IPR036533 (BAG domain + superfamily), IPR000626 (ubiquitin-like).
Crystal structure of the worm BAG domain solved by structural genomics
PMID:15333932.
Notably the worm BAG domain adopts an unusual fold: "the Caenorhabditis elegans BAG
domain is formed by two antiparallel helices, while the third helix is extended away"
PMID:15333932.
The paper infers oligomerization: "stable functional dimers and tetramers can be formed
in solution" PMID:15333932.
UniProt SUBUNIT: "Homodimer or homotetramer" (ECO:0000269|PubMed:15333932).

KNOWN (well-supported) function

BAG-domain co-chaperone / Hsp70(Hsc70) nucleotide-exchange factor (NEF). The
defining activity of the BAG family. Founding paper describing the family (incl. worm
BAG-1/BAG-2) PMID:9873016.
The BAG domain binds the Hsp70 ATPase (nucleotide-binding) domain and drives
ATP-dependent substrate release PMID:15333932.
→ supports GO:0000774 adenyl-nucleotide exchange factor activity, GO:0051087
protein-folding chaperone binding.
Stimulation of Hsc70 ATPase (experimental, worm). Papsdorf, Sacherl & Richter 2014
measured worm BAG proteins as Hsc70 cofactors; C-terminal fragments of UNC-23 perform
"all Hsc70-related functions, like ATPase stimulation and regulation of folding
activity, albeit with lower affinity than BAG-1"
PMID:25053410.
This directly establishes that worm BAG-1 stimulates the Hsc70 ATPase and regulates its
folding activity, with higher affinity than the muscle paralog UNC-23. WormBase used
this paper for the experimental IDA to GO:0001671 ATPase activator activity.
Context: worm Hsc70 (HSP-1) is regulated by two antagonistic cofactor classes — the
J-domain protein DNJ-13 (Hsp40) and the BAG-domain protein UNC-23/BAG-1
PMID:25053410.
Regulation of the Hsp70 folding/refolding cycle (mechanism, from family biology).
BAG proteins act as NEFs that accelerate ADP→ATP exchange, thereby tuning (and, at
excess, antagonizing) the Hsp70 chaperone cycle
PMID:9873016.
UniProt FUNCTION (by similarity): "May inhibit the chaperone activity of HSP70/HSC70 by
promoting substrate release in an ATP-dependent manner."

Localization

No experimental localization for worm BAG-1 in the cached literature. No transmembrane
segment, no signal peptide (KW: Chaperone; 3D-structure; Reference proteome only).
IBA propagates cytoplasm/cytosol (defensible for a soluble co-chaperone), plus nucleus
and membrane from mammalian/fungal orthologs. Human nuclear localization is a property
of the BAG-1L isoform (an N-terminally extended isoform with a nuclear-localization
region); the single short (210 aa) worm protein lacks that N-terminal extension, so the
nucleus IBA is a weak, isoform-driven inference. Membrane is not expected for a soluble
cytosolic NEF with no TM domain.

Interactions (interactome / IPI)

Two HT-Y2H "protein binding" (GO:0005515) IPI annotations both report the same partner
Q9XWX7 = Y43F8B.2, a DUF727-domain protein of largely unknown function
[PMID:14704431 worm interactome WI5; PMID:19123269 WI-2007/WI8]. These are systematic
yeast-two-hybrid maps, not BAG-1-focused studies; UniProt records the interaction
(IntAct EBI-323218/EBI-323231, NbExp=3). GO:0005515 "protein binding" is uninformative
per curation guidelines; the partner is not an Hsp70 and its biological meaning is unclear.

NOT known / knowledge gaps (see review knowledge_gaps)

No in-vivo client/substrate repertoire for worm BAG-1. Whether it channels Hsc70
clients toward refolding vs. proteasomal degradation (as mammalian BAG-1 does via its UBL
domain engaging the 26S proteasome) has not been tested in the worm, despite BAG-1
carrying a UBL domain (FT 8–85).
No loss-of-function phenotype described for bag-1 itself. The muscle-attachment
phenotype in this cofactor system belongs to the paralog unc-23 (BAG2 ortholog), not
bag-1 PMID:25053410.
Whether bag-1 is essential, redundant with unc-23, or has a tissue-restricted role is open.
Direct partner of worm BAG-1 in vivo unconfirmed: family biology predicts HSP-1/Hsc70
binding via the BAG domain, but a physical worm BAG-1–HSP-1 complex has not been
demonstrated in the cached literature (the demonstrated worm Y2H partner is the DUF727
protein Y43F8B.2, biologically unexplained).

Annotation-by-annotation reasoning (summary; see YAML for detail)

GO:0000774 adenyl-nucleotide exchange factor activity (IBA) — ACCEPT, core.
GO:0051087 protein-folding chaperone binding (IBA/IEA/ISS ×3) — ACCEPT (BAG domain binds Hsp70); one kept as core, redundant copies non-core.
GO:0001671 ATPase activator activity (IDA, PMID:25053410) — ACCEPT, core (experimental, worm).
GO:0006457 protein folding (ISS) — KEEP_AS_NON_CORE (co-chaperone regulates the folding cycle; does not itself fold).
GO:0050821 protein stabilization (IBA) — KEEP_AS_NON_CORE (plausible, unverified in worm).
GO:0005737 cytoplasm / GO:0005829 cytosol (IBA) — ACCEPT/KEEP_AS_NON_CORE (soluble co-chaperone).
GO:0005634 nucleus (IBA) — MARK_AS_OVER_ANNOTATED (isoform-specific mammalian property; worm lacks BAG-1L-type N-terminal extension).
GO:0016020 membrane (IBA) — MARK_AS_OVER_ANNOTATED (no TM domain; soluble protein).
GO:0005515 protein binding (IPI ×2, Q9XWX7) — KEEP_AS_NON_CORE (uninformative HT-Y2H interaction).

Cached literature status

All five cited PMIDs are cached; four are abstract-only (9873016, 15333932, 25053410,
14704431), 19123269 has full text (methods/discussion only, no BAG-1 specifics). The single
experimental worm annotation (GO:0001671, PMID:25053410) is supported by the abstract text.

Knowledge-gap statements (plain text, for provenance quoting)

No in-vivo client or substrate has been identified for C. elegans BAG-1, and it is untested whether worm BAG-1 channels Hsc70 clients toward productive refolding or toward proteasomal degradation.
No loss-of-function phenotype has been reported for the bag-1 gene itself in C. elegans, so it is unknown whether bag-1 is essential, redundant with the paralog unc-23, or has a tissue-restricted role.
The only experimentally demonstrated physical partner of worm BAG-1 is the DUF727 protein Y43F8B.2, and a direct BAG-1 to HSP-1/Hsc70 complex in C. elegans has not been shown; the subcellular site of BAG-1 action in the worm is untested.

📄 View Raw YAML

id: O44739
gene_symbol: bag-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  bag-1 encodes the Caenorhabditis elegans member of the BAG (Bcl-2-associated
  athanogene) family of Hsp70/Hsc70 co-chaperones. The 210-residue protein has an
  N-terminal ubiquitin-like domain and a C-terminal BAG domain; the BAG domain
  binds the nucleotide-binding (ATPase) domain of Hsp70-family chaperones and acts
  as a nucleotide-exchange factor, promoting ADP release and ATP-dependent
  discharge of client substrates from the chaperone. By accelerating the
  Hsp70/Hsc70 nucleotide cycle, BAG-1 modulates chaperone-assisted protein
  folding, and at high co-chaperone levels this activity can antagonize productive
  folding. In the worm, BAG-1 stimulates the ATPase activity of the constitutive
  Hsc70 (HSP-1) and, together with the J-domain protein DNJ-13 (Hsp40) and the
  paralogous BAG-domain protein UNC-23 (BAG2 ortholog), belongs to the cofactor
  network that tunes the Hsc70 chaperone cycle. The BAG domain adopts a helical
  bundle fold, and the worm protein can oligomerize into dimers and tetramers. It
  is a soluble, predominantly cytosolic protein.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      InterPro2GO electronic pipeline. The BAG-domain InterPro signatures
      (IPR003103, IPR017093, IPR036533) legitimately map to protein-folding
      chaperone binding, consistent with the experimental and phylogenetic
      evidence.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      GO_Central IBA pipeline. Core molecular-function inferences (nucleotide
      exchange factor activity, chaperone binding) are well founded for a BAG
      protein; some cellular-component propagations (nucleus, membrane) reflect
      mammalian isoform-specific properties not applicable to the single short
      worm protein.
- id: PMID:9873016
  title: An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding paper of the BAG family; explicitly identifies C. elegans BAG-1
      and BAG-2 and establishes that BAG proteins bind the Hsp70/Hsc70 ATPase
      domain and modulate chaperone activity. PubMed-verified; abstract-only in
      cache.
- id: PMID:15333932
  title: 'Structural genomics of Caenorhabditis elegans: structure of the BAG domain.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structure (PDB 1T7S) of the C. elegans BAG-1 BAG domain; states the
      BAG-domain/Hsp70 interaction promotes ATP-dependent substrate release and
      reports an unusual worm BAG fold with dimer/tetramer packing.
      PubMed-verified; abstract-only in cache.
- id: PMID:19123269
  title: Empirically controlled mapping of the Caenorhabditis elegans protein-protein
    interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Genome-scale HT-Y2H interactome (WI-2007/WI8). Source of an IPI protein
      binding annotation to the DUF727 protein Y43F8B.2 (Q9XWX7); systematic
      screen, not a BAG-1-focused study, and the interaction is biologically
      uninterpreted.
- id: PMID:25053410
  title: The balanced regulation of Hsc70 by DNJ-13 and UNC-23 is required for muscle
    functionality.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary C. elegans biochemistry of the Hsc70 cofactor network; the abstract
      states worm BAG-1 has higher affinity than UNC-23 for Hsc70 and that BAG
      C-terminal fragments provide ATPase stimulation and folding regulation.
      Basis for the experimental IDA to ATPase activator activity.
      PubMed-verified; abstract-only in cache.
- id: PMID:14704431
  title: A map of the interactome network of the metazoan C. elegans.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Genome-scale HT-Y2H interactome (WI5). Source of an IPI protein binding
      annotation to Y43F8B.2 (Q9XWX7); systematic screen, not BAG-1-specific, and
      the interaction is biologically uninterpreted.
- id: file:worm/bag-1/bag-1-notes.md
  title: Reviewer notes for C. elegans bag-1
  findings: []
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      BAG-1 is a soluble co-chaperone that acts on cytoplasmic Hsp70/Hsc70;
      cytoplasmic localization is expected and consistent with the absence of any
      transmembrane or signal-peptide features.
    action: ACCEPT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Nuclear localization in the BAG family is a property of the mammalian
      BAG-1L isoform, which carries an N-terminal extension bearing a
      nuclear-localization region. The single 210-residue worm protein lacks that
      extension and there is no experimental evidence for nuclear BAG-1 in C.
      elegans, so this phylogenetically propagated term likely over-annotates an
      isoform-specific mammalian feature.
    action: MARK_AS_OVER_ANNOTATED
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
        - COMPARTMENT_OR_COMPLEX_MISMATCH
        - FUNCTIONAL_DIVERGENCE
      source_entities:
        - source_id: PANTHER:PTN000269156
          source_label: BAG family node (nucleus IBA source)
          source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
          comment: >-
            Nuclear localization derives from the N-terminally extended mammalian
            BAG-1L isoform; the single short worm protein lacks that
            nuclear-targeting extension, so the source annotation is sound but does
            not transfer.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Cytosol is a more precise and appropriate location for a soluble BAG-domain
      nucleotide-exchange factor acting on cytosolic Hsc70; consistent with the
      lack of membrane or organelle-targeting features.
    action: ACCEPT
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Worm BAG-1 has no transmembrane segment, no signal peptide, and no
      lipid-anchor features; it is a soluble cytosolic co-chaperone. The membrane
      term is a weak phylogenetic propagation (partly from a BAG3-type ortholog)
      and is not expected to apply to this protein.
    action: MARK_AS_OVER_ANNOTATED
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
        - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
        - source_id: PANTHER:PTN000269156
          source_label: BAG family node (membrane IBA source)
          source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
          comment: >-
            Membrane association is not expected for a soluble BAG-domain NEF with
            no transmembrane segment or lipid anchor; the term is partly propagated
            from a BAG3-type ortholog and does not transfer to this protein.
- term:
    id: GO:0000774
    label: adenyl-nucleotide exchange factor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      This is the defining molecular function of the BAG family: the BAG domain
      binds the Hsp70/Hsc70 ATPase domain and promotes ADP release / ATP-dependent
      substrate discharge, i.e. nucleotide exchange. Well supported by family
      biology and the worm structure, and consistent with the experimental Hsc70
      ATPase stimulation measured for worm BAG-1.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15333932
      supporting_text: >-
        Binding of the BAG domain to the eukaryotic chaperone heat-shock protein
        (Hsp70) promotes ATP-dependent release of the protein substrate from
        Hsp70.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Plausible downstream consequence of BAG-1's modulation of the Hsp70/Hsc70
      cycle, propagated from mammalian orthologs. No worm-specific evidence that
      BAG-1 stabilizes particular clients, so retained as a non-core biological
      process.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Binding to the Hsp70/Hsc70 chaperone via the BAG domain is central to BAG-1
      function and is the enabling interaction underlying its nucleotide-exchange
      activity. Well supported for a BAG-domain protein.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9873016
      supporting_text: >-
        BAG-1 binds the ATPase domains of Hsp70 and Hsc70, modulating their
        chaperone activity and functioning as a competitive antagonist of the
        co-chaperone Hip
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation from the BAG-domain signatures.
      Correctly captures Hsp70/Hsc70 chaperone binding and corroborates the
      phylogenetic and experimental support for this interaction (an independent
      evidence line for the same accepted chaperone-binding function).
    action: ACCEPT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14704431
  qualifier: enables
  review:
    summary: >-
      High-throughput yeast-two-hybrid interaction with the DUF727 protein
      Y43F8B.2 (Q9XWX7), a partner of unknown function that is not an Hsp70. The
      generic "protein binding" term is uninformative about BAG-1's molecular
      function; retained as a real but non-core experimental interaction.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:14704431
      supporting_text: >-
        more than 4000 interactions were identified from high-throughput, yeast
        two-hybrid (HT=Y2H) screens
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19123269
  qualifier: enables
  review:
    summary: >-
      Second high-throughput yeast-two-hybrid report of the same Y43F8B.2
      (Q9XWX7) interaction. As above, the generic "protein binding" term is
      uninformative about function; retained as a non-core experimental
      interaction rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:19123269
      supporting_text: >-
        We present an expanded C. elegans protein-protein interaction network, or
        'interactome' map, derived from testing a matrix of approximately 10,000 x
        approximately 10,000 proteins using a highly specific, high-throughput
        yeast two-hybrid system.
- term:
    id: GO:0001671
    label: ATPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:25053410
  qualifier: enables
  review:
    summary: >-
      Experimentally supported for worm BAG-1: as a nucleotide-exchange factor it
      accelerates the Hsc70 ATPase cycle. Papsdorf et al. measured ATPase
      stimulation and folding regulation for the BAG cofactors and report that
      BAG-1 acts with higher affinity than the paralog UNC-23. This mechanistically
      complements the nucleotide-exchange-factor annotation and is a core function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:25053410
      supporting_text: >-
        C-terminal fragments of UNC-23 instead perform all Hsc70-related
        functions, like ATPase stimulation and regulation of folding activity,
        albeit with lower affinity than BAG-1
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: ISS
  original_reference_id: PMID:9873016
  qualifier: involved_in
  review:
    summary: >-
      As an Hsp70/Hsc70 co-chaperone that regulates the ATP-driven folding cycle,
      BAG-1 is legitimately involved in the protein-folding process; the
      involved_in qualifier does not imply it is itself a foldase (indeed excess
      BAG can inhibit chaperone activity). The specific regulatory mechanism is
      captured by the nucleotide-exchange-factor and ATPase-activator annotations.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:9873016
      supporting_text: >-
        The human BAG-1, BAG-2, and BAG-3 proteins bind with high affinity (KD
        congruent with 1-10 nM) to the ATPase domain of Hsc70 and inhibit its
        chaperone activity in a Hip-repressible manner
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: ISS
  original_reference_id: PMID:15333932
  qualifier: enables
  review:
    summary: >-
      Sequence/structure-based inference of Hsp70 chaperone binding, supported by
      the crystal structure of the worm BAG domain and its documented role in
      Hsp70-dependent substrate release. An independent evidence line for the same
      accepted chaperone-binding function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15333932
      supporting_text: >-
        Binding of the BAG domain to the eukaryotic chaperone heat-shock protein
        (Hsp70) promotes ATP-dependent release of the protein substrate from
        Hsp70.
core_functions:
- description: >-
    BAG-1 is a BAG-domain co-chaperone that acts as a nucleotide-exchange factor
    (NEF) for cytosolic Hsp70/Hsc70 (worm HSP-1). Its C-terminal BAG domain binds
    the chaperone's nucleotide-binding (ATPase) domain and promotes ADP release,
    accelerating the ATP-driven cycle and ATP-dependent discharge of client
    substrates. Experimentally, worm BAG-1 stimulates the Hsc70 ATPase (with
    higher affinity than the paralog UNC-23), and thereby tunes chaperone-assisted
    folding; the same activity can antagonize the chaperone when the cofactor is in
    excess.
  molecular_function:
    id: GO:0000774
    label: adenyl-nucleotide exchange factor activity
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:15333932
    supporting_text: >-
      Binding of the BAG domain to the eukaryotic chaperone heat-shock protein
      (Hsp70) promotes ATP-dependent release of the protein substrate from Hsp70.
  - reference_id: PMID:9873016
    supporting_text: >-
      BAG-1 binds the ATPase domains of Hsp70 and Hsc70, modulating their
      chaperone activity and functioning as a competitive antagonist of the
      co-chaperone Hip
  - reference_id: PMID:25053410
    supporting_text: >-
      C-terminal fragments of UNC-23 instead perform all Hsc70-related functions,
      like ATPase stimulation and regulation of folding activity, albeit with
      lower affinity than BAG-1
knowledge_gaps:
- gap_statement: >-
    No in-vivo client or substrate of C. elegans BAG-1 has been identified, and it
    is untested whether worm BAG-1 biases Hsc70-bound clients toward productive
    refolding or, via its ubiquitin-like domain, toward proteasomal degradation
    (the folding-versus-degradation decision that mammalian BAG-1 helps make).
  boundary: >-
    It is firmly established that BAG-1 is a BAG-domain nucleotide-exchange factor
    that binds the Hsp70/Hsc70 ATPase domain, stimulates the Hsc70 ATPase, and
    promotes ATP-dependent substrate release, and that it carries an N-terminal
    ubiquitin-like domain. What clients pass through this activity in the worm, and
    what fate BAG-1 directs them to, are unknown.
  gap_kind:
  - BIOLOGY
  dark_aspect: BP_DARK
  status: OPEN
  significance: >-
    The functional output of an Hsp70 NEF depends entirely on which clients it
    engages and whether it promotes their folding or clearance; without this, the
    worm-specific biological role of BAG-1 cannot be assigned, and its relationship
    to proteostasis-network aging phenotypes remains inferential.
  resolution: >-
    Affinity-proteomics / co-immunoprecipitation of BAG-1 (and BAG-1-vs-UNC-23) from
    C. elegans to define native clients, combined with degradation/refolding
    reporter assays and tests of the ubiquitin-like-domain proteasome link, would
    close the gap.
  provenance:
  - reference_id: PMID:9873016
    supporting_text: >-
      The mechanisms by which Hsp70 family chaperones are regulated, however, are
      only partly understood.
  - reference_id: file:worm/bag-1/bag-1-notes.md
    supporting_text: >-
      No in-vivo client or substrate has been identified for C. elegans BAG-1, and
      it is untested whether worm BAG-1 channels Hsc70 clients toward productive
      refolding or toward proteasomal degradation.
- gap_statement: >-
    No loss-of-function phenotype has been reported for the bag-1 gene itself in C.
    elegans, so it is unknown whether bag-1 is essential, is functionally redundant
    with its paralog unc-23, or has a distinct tissue-restricted role.
  boundary: >-
    In this cofactor system the characterized in-vivo phenotype (severe motility
    dysfunction, muscle-attachment-site localization) belongs to the paralog
    UNC-23/BAG2, whereas BAG-1 has only been characterized biochemically (higher
    Hsc70 affinity than UNC-23). A bag-1 mutant or RNAi phenotype is not described in
    the cached literature.
  gap_kind:
  - BIOLOGY
  dark_aspect: BP_DARK
  status: OPEN
  significance: >-
    Whether bag-1 is dispensable, buffered by unc-23, or independently required in a
    particular tissue determines its true biological role and its weight in the worm
    proteostasis network.
  resolution: >-
    Characterization of a bag-1 deletion/RNAi (alone and in a unc-23 background) for
    viability, motility, stress resistance, and proteostasis reporters would define
    the biological role and test redundancy with unc-23.
  provenance:
  - reference_id: PMID:25053410
    supporting_text: >-
      one of them being UNC-23, whose mutation induces severe motility dysfunctions
  - reference_id: file:worm/bag-1/bag-1-notes.md
    supporting_text: >-
      No loss-of-function phenotype has been reported for the bag-1 gene itself in
      C. elegans, so it is unknown whether bag-1 is essential, redundant with the
      paralog unc-23, or has a tissue-restricted role.
- gap_statement: >-
    A direct physical BAG-1-to-HSP-1/Hsc70 complex in C. elegans has not been
    demonstrated, and the subcellular site of BAG-1 action in the worm is untested;
    the only experimentally reported worm partner is the DUF727 protein Y43F8B.2,
    whose functional relationship to BAG-1 is unexplained.
  boundary: >-
    Family biology and the worm BAG-domain crystal structure predict binding to the
    Hsp70/Hsc70 ATPase domain, and biochemistry shows worm BAG-1 stimulates Hsc70;
    but the demonstrated worm two-hybrid partner is Y43F8B.2, not HSP-1, and no
    localization data exist for endogenous BAG-1.
  gap_kind:
  - BIOLOGY
  - CURATION
  dark_aspect: CC_DARK
  status: OPEN
  significance: >-
    Establishing the physiological BAG-1/Hsc70 complex and where it forms would
    convert the inferred co-chaperone role into a directly evidenced one and clarify
    the meaning (if any) of the Y43F8B.2 interaction.
  resolution: >-
    Co-immunoprecipitation or proximity labeling of endogenous BAG-1 with HSP-1, plus
    a tagged-BAG-1 expression/localization reporter, would confirm the complex and its
    site of action.
  provenance:
  - reference_id: PMID:15333932
    supporting_text: >-
      The structure may represent a new folding type of the BAG domain.
  - reference_id: file:worm/bag-1/bag-1-notes.md
    supporting_text: >-
      The only experimentally demonstrated physical partner of worm BAG-1 is the
      DUF727 protein Y43F8B.2, and a direct BAG-1 to HSP-1/Hsc70 complex in C.
      elegans has not been shown; the subcellular site of BAG-1 action in the worm
      is untested.
suggested_questions:
- question: >-
    Does C. elegans BAG-1 form a physiological complex with the constitutive Hsc70
    HSP-1, and is this interaction functionally distinct from that of the paralog
    UNC-23?
- question: >-
    Does BAG-1 direct Hsc70 clients toward refolding or toward proteasomal
    degradation, and does its ubiquitin-like domain mediate a proteasome link as in
    mammalian BAG-1?
suggested_experiments:
- description: >-
    Generate and phenotype a bag-1 loss-of-function allele (CRISPR deletion or RNAi),
    alone and combined with unc-23 loss, assaying viability, motility,
    thermotolerance, and aggregation/proteostasis reporters to test whether bag-1 has
    an independent role or is redundant with unc-23.
- description: >-
    Affinity-purify tagged BAG-1 from worm lysates followed by mass spectrometry to
    define the native BAG-1 interactome (HSP-1/Hsc70 and clients), and combine with
    in-vitro Hsc70 ATPase and luciferase refolding assays to quantify BAG-1's effect
    on the chaperone cycle.

bag-1

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

📚 Additional Documentation

Notes

bag-1 (C. elegans) research notes

Identity check

Domain architecture / structure

KNOWN (well-supported) function

Localization

Interactions (interactome / IPI)

NOT known / knowledge gaps (see review knowledge_gaps)

Annotation-by-annotation reasoning (summary; see YAML for detail)

Cached literature status

Knowledge-gap statements (plain text, for provenance quoting)

📄 View Raw YAML