SSA4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically inferred nuclear localization. For Ssa4 this is consistent with experimentally observed, but conditional, nuclear accumulation during starvation (PMID:11279056) and cadmium stress (PMID:39456809); it is not the default site of chaperone function. Reason: Nuclear localization is a real but starvation/cadmium-stress-conditional relocalization, not the core cytosolic site of function. Supporting Evidence: PMID:11279056 the hsp70 Ssa4p concentrates in nuclei upon starvation. Nuclear concentration of Ssa4p in starving cells is reversible file:yeast/SSA4/SSA4-deep-research-falcon.md Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70 PMID:39456809 ScSSA4 binds to POre Membrane 34 (POM34), a key component of nuclear pore complex (NPC), and translocates from the cytoplasm to the nucleus, where it regulates the expression of its downstream gene, Viable in a Hal3 Sit4 background 1 (VHS1), resulting in reduced Cd accumulation in yeast cells.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cytoplasm is the core localization of Ssa4, consistent with UniProt and falcon synthesis classifying Ssa4 as a cytosolic/cytoplasmic Hsp70. Reason: Core cytoplasmic localization, well supported across sources. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70
GO:0005886 plasma membrane	IBA GO_REF:0000033	REMOVE	Summary: Plasma membrane is not a supported site of Ssa4 function. Ssa4 is the stress-inducible cytosolic Hsp70 paralog, and neither UniProt nor the SSA4-focused literature synthesis supports a plasma-membrane pool. Reason: The pinned 2025 GOA row points to PAINT node PTN002500132, but the current local PTHR19375 PAINT snapshot retains nucleus and cytosol at that node and no longer carries GO:0005886. The stale inference also lacks target-specific corroboration: Ssa4 is directly observed in cytoplasm and conditionally in nucleus. Propagation Review Root cause: SOURCE STALE OR MISSING Sources checked: PANTHER:PTN002500132 · PAINT Hsp70 family node SOURCE STALE OR MISSING The current PTHR19375 PAINT snapshot has nucleus and cytosol IBD rows at this node but no plasma-membrane IBD row; the pinned GOA transfer is therefore stale. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: ATP hydrolysis drives the Hsp70 substrate-binding/release cycle. Ssa4 is an ATP-dependent molecular chaperone with the canonical Hsp70 nucleotide-binding domain (NBD); ATP hydrolysis activity captures the catalytic component of the chaperone cycle. Note that the unified molecular function is better expressed as ATP-dependent protein folding chaperone (GO:0140662; see core_functions). Reason: Core catalytic activity underlying the ATP-dependent chaperone cycle of this Hsp70. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md SSA4 encodes an ATP-dependent molecular chaperone (Hsp70 family) rather than an enzyme with a discrete small-molecule substrate.
GO:0031072 heat shock protein binding	IBA GO_REF:0000033	ACCEPT	Summary: Ssa4 engages other heat shock proteins and cochaperones (e.g., the J-protein/Hsp40 Sis1, the NEF Sse1, and paralogs Ssa2/Ssa3, all recorded as UniProt INTERACTION partners) and cooperates with the Hsp104 disaggregase. Falcon notes inter-isoform variation is concentrated in an NBD surface implicated in J-protein cochaperone interactions, supporting cochaperone/heat-shock-protein binding. Reason: Heat-shock-protein binding is an integral part of the Hsp70 cochaperone machinery represented in the core-function description, although it is not a separate catalytic core function. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md cooperation with disaggregation machinery (notably Hsp104 in yeast).
GO:0044183 protein folding chaperone	IBA GO_REF:0000033	MODIFY	Summary: Core molecular function. Ssa4 is a protein folding chaperone that binds exposed hydrophobic segments of client proteins to assist folding/refolding of nascent or stress-damaged polypeptides. Falcon supports this directly; the ATP-dependent child term GO:0140662 (ATP-dependent protein folding chaperone) is the most precise MF and is used in core_functions. Reason: The family-level chaperone term is correct but less precise than the experimentally supported ATP-dependent Hsp70 mechanism; replace it with GO:0140662. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000452648 · PAINT Hsp70 family node SUPPORTS TRANSFER The family transfer correctly identifies chaperone activity in Ssa4, but GO:0140662 captures its ATP-dependent mechanism more precisely. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md assisting folding/refolding of nascent or stress-damaged proteins;
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosol is the primary site of action for Ssa4. Falcon deep research confirms Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70, consistent with UniProt (SUBCELLULAR LOCATION: Cytoplasm). Reason: Core localization. Cytosolic Ssa-family Hsp70 strongly supported by literature synthesis. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process. As a stress-inducible Hsp70, Ssa4 contributes to refolding of stress-denatured proteins and cooperates with the Hsp104 disaggregase to recover proteins from aggregates following heat shock. Reason: Core process for a stress-inducible chaperone; well supported by Hsp70/Hsp104 disaggregation biology. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md cooperation with disaggregation machinery (notably Hsp104 in yeast).
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MODIFY	Summary: Nucleotide (ATP/ADP) binding at the Hsp70 N-terminal nucleotide-binding domain. A more specific, equivalent annotation (GO:0005524 ATP binding) is also present. Consistent with the conserved Hsp70 NBD architecture. Reason: Nucleotide binding is correct but too broad for the Hsp70 nucleotide-binding domain; replace it with the existing, mechanistically specific ATP-binding term. Proposed replacements: ATP binding Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md an N-terminal nucleotide-binding domain (NBD)
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: ATP binding at the Hsp70 N-terminal nucleotide-binding domain (NBD) is required for the chaperone substrate-binding/release cycle. Supported by UniProt ATP-binding keyword and the conserved Hsp70 NBD architecture. Reason: Well-supported molecular function intrinsic to the Hsp70 NBD. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md Hsp70 proteins have a canonical domain architecture consisting of an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD) connected by a flexible linker.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Cytoplasm localization, consistent with UniProt and falcon synthesis (cytosolic Hsp70). Duplicates the IBA/IDA cytoplasm annotations. Reason: Core cytoplasmic localization, consistent across automated and manual sources. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70
GO:0006457 protein folding	IEA GO_REF:0000117	ACCEPT	Summary: Core biological process. Ssa4 assists folding/refolding of nascent and stress-damaged proteins as part of the cytosolic Hsp70 chaperone network. Reason: Core chaperone process strongly supported by Hsp70 family biology and literature synthesis. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md assisting folding/refolding of nascent or stress-damaged proteins;
GO:0006616 SRP-dependent cotranslational protein targeting to membrane, translocation	IEA GO_REF:0000117	MODIFY	Summary: Same mechanistic correction as the IMP GO:0006616 entry. Cytosolic Ssa Hsp70 (with Ydj1) functions in the SRP-INDEPENDENT post-translational translocation pathway, not the SRP-dependent cotranslational route. Modify to GO:0031204 (post-translational protein targeting to membrane, translocation). This is a non-core, ancillary role relative to the protein's core folding/refolding chaperone function. Reason: ARBA-inferred SRP-dependent cotranslational term is the wrong mechanism for yeast Ssa Hsp70, which mediates post-translational translocation. Proposed replacements: post-translational protein targeting to membrane, translocation Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md The Ssa family broadly supports folding, translocation, and degradation
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: ATP hydrolysis activity of the Hsp70 NBD; duplicates the IBA GO:0016887 annotation. The unified core molecular function is better captured as GO:0140662 (ATP-dependent protein folding chaperone). Reason: Accurate catalytic activity intrinsic to the Hsp70 chaperone cycle. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md SSA4 encodes an ATP-dependent molecular chaperone (Hsp70 family) rather than an enzyme with a discrete small-molecule substrate.
GO:0051082 unfolded protein binding	IEA GO_REF:0000117	MODIFY	Summary: Unfolded protein binding accurately describes the Hsp70 substrate-binding domain engaging non-native polypeptides exposing hydrophobic segments. It is retained but modified toward the ATP-dependent chaperone activity that unifies binding with the productive folding outcome (the catalytic role is what is evolutionarily selected). Reason: Unfolded protein binding is correct but is the binding component of the broader ATP-dependent chaperone activity; the protein folding chaperone term better captures the core enabled function. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md Its “substrate specificity” is primarily proteins/peptides exposing hydrophobic segments, typical of unfolded or partially folded polypeptides.
GO:0005515 protein binding	IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine...	MODIFY	Summary: This row records an Ssa4-Ssa2 interaction (WITH/FROM UniProtKB:P10592). The generic protein-binding term discards the Hsp70 identity of the partner. The source is a genome-wide affinity-purification/mass-spectrometry complex survey, so this row does not by itself establish direct binary contact. Reason: Replace generic protein binding with GO:0030544 Hsp70 protein binding. Proposed replacements: Hsp70 protein binding
GO:0005515 protein binding	IPI PMID:17892321 Structure-templated predictions of novel protein interaction...	MODIFY	Summary: This row records an Ssa4-Sis1 interaction (WITH/FROM UniProtKB:P25294). Sis1 is an Hsp40/J-domain cochaperone rather than an unspecified binding partner. The paper predicts interactions from structural motifs and sequence and tests only a subset; the specific Ssa4-Sis1 edge is not individually narrated in the main text. Reason: Replace generic protein binding with GO:0031072 heat shock protein binding. Proposed replacements: heat shock protein binding
GO:0005515 protein binding	IPI PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ...	MODIFY	Summary: This partner-specific row records Ssa3 (WITH/FROM UniProtKB:P09435), another cytosolic Ssa-family Hsp70. The study's TAP interactions may be indirect complexes. Reason: Replace generic protein binding with GO:0030544 Hsp70 protein binding. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:19536198 It should be emphasized that the interactions presented are indirect TAP-tag based interactions and not direct binary interactions.
GO:0005515 protein binding	IPI PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ...	MODIFY	Summary: This separate row records Ssa2 (WITH/FROM UniProtKB:P10592), an Hsp70 paralog; the TAP interaction may represent a shared chaperone complex rather than direct contact. Reason: Replace generic protein binding with GO:0030544 Hsp70 protein binding. Proposed replacements: Hsp70 protein binding Supporting Evidence: PMID:19536198 It should be emphasized that the interactions presented are indirect TAP-tag based interactions and not direct binary interactions.
GO:0005515 protein binding	IPI PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ...	MODIFY	Summary: This separate row records Sse1 (WITH/FROM UniProtKB:P32589), the Hsp110-family nucleotide-exchange factor that participates in Hsp70 chaperone complexes. Reason: Replace generic protein binding with GO:0031072 heat shock protein binding. Proposed replacements: heat shock protein binding Supporting Evidence: PMID:19536198 It should be emphasized that the interactions presented are indirect TAP-tag based interactions and not direct binary interactions.
GO:0005515 protein binding	IPI PMID:31454312 The role of structural pleiotropy and regulatory evolution i...	MODIFY	Summary: This row records interaction with the paralog Ssa3 (WITH/FROM UniProtKB:P09435), so the partner class is known even though the existing term is generic. The paper analyzes paralog heteromers as a class, and the specific edge is not individually narrated in its main text. Reason: Replace generic protein binding with GO:0030544 Hsp70 protein binding. Proposed replacements: Hsp70 protein binding
GO:0005515 protein binding	IPI PMID:37968396 The social and structural architecture of the yeast protein ...	MODIFY	Summary: This row records interaction with Ssa2 (WITH/FROM UniProtKB:P10592), an Hsp70 paralog, in a high-throughput affinity-enrichment/mass-spectrometry interactome; this is dataset-level evidence rather than a targeted binary assay. Reason: Replace generic protein binding with GO:0030544 Hsp70 protein binding. Proposed replacements: Hsp70 protein binding
GO:0005515 protein binding	IPI PMID:37968396 The social and structural architecture of the yeast protein ...	MODIFY	Summary: This separate row records interaction with the Hsp40/J-domain cochaperone Sis1 (WITH/FROM UniProtKB:P25294) in a high-throughput affinity-enrichment/mass- spectrometry interactome; this is dataset-level evidence rather than a targeted binary assay. Reason: Replace generic protein binding with GO:0031072 heat shock protein binding. Proposed replacements: heat shock protein binding
GO:0005515 protein binding	IPI PMID:37968396 The social and structural architecture of the yeast protein ...	MODIFY	Summary: This separate row records interaction with the Hsp110 nucleotide-exchange factor Sse1 (WITH/FROM UniProtKB:P32589) in a high-throughput affinity-enrichment/mass- spectrometry interactome; this is dataset-level evidence rather than a targeted binary assay. Reason: Replace generic protein binding with GO:0031072 heat shock protein binding. Proposed replacements: heat shock protein binding
GO:0005634 nucleus	IDA PMID:11279056 Starvation promotes nuclear accumulation of the hsp70 Ssa4p ...	KEEP AS NON CORE	Summary: Nuclear localization of Ssa4 is real but conditional: Chughtai et al. (2001) show Ssa4p concentrates in nuclei specifically upon starvation (reversible, with active export on refeeding) via an N-terminal Star sequence and the beta-importin Nmd5p. Zheng et al. (2024) independently show nuclear translocation under cadmium stress, association with Pom34, and regulation of VHS1 expression linked to reduced cadmium accumulation. These are context-specific relocalizations rather than the default site of chaperone action, so nucleus is retained as non-core. Falcon confirms Ssa4 is otherwise classified as a cytosolic/cytoplasmic Hsp70. Reason: Starvation- and cadmium-induced nuclear accumulation are real but context-specific localizations, not the core cytosolic site of chaperone function. Supporting Evidence: PMID:11279056 the hsp70 Ssa4p concentrates in nuclei upon starvation. Nuclear concentration of Ssa4p in starving cells is reversible file:yeast/SSA4/SSA4-deep-research-falcon.md Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70 PMID:39456809 ScSSA4 binds to POre Membrane 34 (POM34), a key component of nuclear pore complex (NPC), and translocates from the cytoplasm to the nucleus, where it regulates the expression of its downstream gene, Viable in a Hal3 Sit4 background 1 (VHS1), resulting in reduced Cd accumulation in yeast cells.
GO:0005737 cytoplasm	IDA PMID:11279056 Starvation promotes nuclear accumulation of the hsp70 Ssa4p ...	ACCEPT	Summary: Cytoplasm is the default, core localization of Ssa4; conditional nuclear accumulation occurs during starvation and cadmium stress (see GO:0005634). Consistent with UniProt (SUBCELLULAR LOCATION: Cytoplasm) and falcon synthesis. Reason: Core cytoplasmic/cytosolic localization for this Hsp70, directly observed and consistent across sources. Supporting Evidence: file:yeast/SSA4/SSA4-deep-research-falcon.md Ssa4 is consistently classified as a cytosolic/cytoplasmic Hsp70
GO:0006457 protein folding	IGI PMID:9789005 Folding in vivo of a newly translated yeast cytosolic enzyme...	ACCEPT	Summary: This SSA1-linked genetic row (WITH/FROM SGD:S000000004) derives from Kim et al. (1998), who show the SSA class of cytosolic Hsp70 mediates folding of newly translated cytosolic enzymes (e.g., OTC); in vitro refolding was specifically directed by Ssa1/2, while the in vivo SSA-deficiency phenotype is a class-level result. The annotation to SSA4 reflects membership in the functionally redundant Ssa class rather than a distinct Ssa4-specific mechanism, but the chaperone folding role is genuine for the inducible paralog. Reason: Core chaperone folding role; SSA-class genetic evidence applies to Ssa4 as a member of the redundant subfamily. Supporting Evidence: PMID:9789005 we observe that yeast cytosolic OTC is assisted to its native state by the SSA class of yeast cytosolic Hsp70 proteins. file:yeast/SSA4/SSA4-deep-research-falcon.md assisting folding/refolding of nascent or stress-damaged proteins;
GO:0006457 protein folding	IGI PMID:9789005 Folding in vivo of a newly translated yeast cytosolic enzyme...	ACCEPT	Summary: This separate genetic-interaction row is linked to SSA3 (WITH/FROM SGD:S000000171). The class-level experiment supports a genuine, redundant Ssa-family folding role. Reason: Core chaperone folding role supported by SSA-class genetic evidence. Supporting Evidence: PMID:9789005 we observe that yeast cytosolic OTC is assisted to its native state by the SSA class of yeast cytosolic Hsp70 proteins.
GO:0006457 protein folding	IGI PMID:9789005 Folding in vivo of a newly translated yeast cytosolic enzyme...	ACCEPT	Summary: This separate genetic-interaction row is linked to SSA2 (WITH/FROM SGD:S000003947). The class-level experiment supports a genuine, redundant Ssa-family folding role. Reason: Core chaperone folding role supported by SSA-class genetic evidence. Supporting Evidence: PMID:9789005 we observe that yeast cytosolic OTC is assisted to its native state by the SSA class of yeast cytosolic Hsp70 proteins.
GO:0006616 SRP-dependent cotranslational protein targeting to membrane, translocation	IMP PMID:8754838 Functional interaction of cytosolic hsp70 and a DnaJ-related...	MODIFY	Summary: The cited evidence (Becker et al. 1996) shows that the SSA class of cytosolic Hsp70, together with the Hsp40/DnaJ cochaperone Ydj1, supports POST-TRANSLATIONAL translocation of selected ER precursors, with a rapid direct effect on prepro-alpha-factor import. The assigned term "SRP-dependent cotranslational protein targeting" is therefore mislabeled with respect to mechanism: yeast Ssa Hsp70/Ydj1 act in the post-translational, not the SRP-dependent cotranslational, route. The annotation should be modified to GO:0031204 (post-translational protein targeting to membrane, translocation), and remains a non-core, class-level role (the experiments used a ssa1ts ssa2 ssa3 ssa4 background, so the role reflects the redundant Ssa class rather than Ssa4 alone). The paper also reports a mitochondrial precursor phenotype, but that broader effect is not encoded by this ER-scoped replacement. Reason: Cited evidence describes SRP-independent post-translational translocation via Ssa Hsp70/Ydj1; the current term asserts the SRP-dependent cotranslational pathway, which is the wrong mechanism. Proposed replacements: post-translational protein targeting to membrane, translocation Supporting Evidence: PMID:8754838 Functional interaction of cytosolic hsp70 and a DnaJ-related protein, Ydj1p, in protein translocation in vivo. PMID:8754838 The processing of prepro-alpha-factor was inhibited within 2 min of the shift to 37 degrees C, suggesting a direct effect of the hsp70 defect on translocation.
GO:0051082 unfolded protein binding	IGI PMID:9789005 Folding in vivo of a newly translated yeast cytosolic enzyme...	MODIFY	Summary: This SSA1-linked genetic row (WITH/FROM SGD:S000000004) has the same rationale as the IEA GO:0051082 entry: binding of non-native/unfolded clients is accurate (Kim et al. show SSA-class Hsp70 assists folding of newly translated cytosolic enzymes) but is best represented as the unified ATP-dependent protein folding chaperone activity. Reason: Unfolded protein binding is the binding component of the broader chaperone activity; protein folding chaperone better captures the enabled core function. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: PMID:9789005 we observe that yeast cytosolic OTC is assisted to its native state by the SSA class of yeast cytosolic Hsp70 proteins. file:yeast/SSA4/SSA4-deep-research-falcon.md binding exposed hydrophobic segments in client proteins;
GO:0051082 unfolded protein binding	IGI PMID:9789005 Folding in vivo of a newly translated yeast cytosolic enzyme...	MODIFY	Summary: This separate SSA3-linked genetic row (WITH/FROM SGD:S000000171) supports Ssa-family client handling, but the legacy binding term omits ATP-dependent activity. Reason: Replace the binding-only term with the unified ATP-dependent chaperone activity. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: PMID:9789005 we observe that yeast cytosolic OTC is assisted to its native state by the SSA class of yeast cytosolic Hsp70 proteins.
GO:0051082 unfolded protein binding	IGI PMID:9789005 Folding in vivo of a newly translated yeast cytosolic enzyme...	MODIFY	Summary: This separate SSA2-linked genetic row (WITH/FROM SGD:S000003947) supports Ssa-family client handling, but the legacy binding term omits ATP-dependent activity. Reason: Replace the binding-only term with the unified ATP-dependent chaperone activity. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: PMID:9789005 we observe that yeast cytosolic OTC is assisted to its native state by the SSA class of yeast cytosolic Hsp70 proteins.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

OpenScientist

📚 Additional Documentation

Notes

📄 View Raw YAML