HSP104

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: HSP104 is well-established to localize to the cytoplasm, confirmed by immunoelectron microscopy (PMID:10467108) and high-throughput GFP-tagging (PMID:14562095 via UniProt). The IBA annotation is consistent with multiple lines of direct experimental evidence. Reason: HSP104 cytoplasmic localization is its primary site of action for protein disaggregation. Confirmed by IDA (PMID:10467108): "a small amount of Hsp104 was located in the cytoplasm and nucleus" and by HDA (PMID:22842922). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000181243 · PANTHER:PTN000181243 SUPPORTS TRANSFER The PTHR11638 PAINT record places cytoplasm at this broad family node using experimentally localized fungal, bacterial, plant, and protist descendants, including S. cerevisiae HSP104 itself. Supporting Evidence: PMID:10467108 At normal temperature (25 degrees C), a small amount of Hsp104 was located in the cytoplasm and nucleus.
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: HSP104 is a well-characterized ATPase with two AAA-type nucleotide-binding domains per monomer. ATP hydrolysis is central to its disaggregase function. Extensive biochemical characterization (PMID:9624144, PMID:11782421, PMID:16135516) demonstrates robust ATPase activity. Reason: ATP hydrolysis is a core enzymatic activity of HSP104, required for its protein disaggregation mechanism. Supported by multiple IDA and IMP annotations. PMID:16135516 directly demonstrates ATPase activity and its regulation by substrate binding. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000181243 · PANTHER:PTN000181243 SUPPORTS TRANSFER ATP hydrolysis is conserved across the PTHR11638 AAA+ family and HSP104 is itself among the experimentally grounded descendants. Supporting Evidence: PMID:16135516 upon association with a polypeptide, a conformational change occurs within Hsp104 that strongly reduces the dynamics of nucleotide exchange and commits the bound polypeptide to ATP hydrolysis.
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	Summary: HSP104 participates in protein refolding, though it does so indirectly -- it solubilizes aggregated proteins and hands them off to Hsp70/Hsp40 for actual refolding (PMID:9674429). The IBA annotation is reasonable as HSP104 is required for the overall refolding process. Reason: While HSP104 itself does not refold proteins (that is done by Hsp70/40), it is an essential component of the refolding pathway by extracting substrates from aggregates. PMID:9674429 demonstrates that "in concert with Hsp40 and Hsp70, Hsp104 can reactivate proteins that have been denatured and allowed to aggregate." The annotation to the BP "protein refolding" is appropriate. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN007521008 · PANTHER:PTN007521008 SUPPORTS TRANSFER The fungal node is seeded by the experimentally characterized S. pombe ortholog; HSP104's direct reactivation studies independently support participation in protein refolding. Supporting Evidence: PMID:9674429 in concert with Hsp40 and Hsp70, Hsp104 can reactivate proteins that have been denatured and allowed to aggregate, substrates refractory to the action of other chaperones.
GO:0043335 protein unfolding	IBA GO_REF:0000033	ACCEPT	Summary: HSP104 unfolds/threads aggregated proteins through its central pore as part of its disaggregation mechanism (PMID:15128736, PMID:18312264). This is a core aspect of the disaggregation mechanism. Reason: Protein unfolding is mechanistically integral to HSP104 disaggregase function. The threading mechanism requires unfolding substrates to pass through the narrow central pore of the hexamer. Supported by PMID:18312264 "Substrate threading through the central pore of the Hsp104 chaperone as a common mechanism for protein disaggregation." Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN007521008 · PANTHER:PTN007521008 SUPPORTS TRANSFER The fungal node is grounded by S. pombe and S. cerevisiae descendants, and substrate threading directly establishes this conserved process for HSP104. Supporting Evidence: PMID:7984243 Hsp104 functions in a manner not previously described for other heat-shock proteins: it mediates the resolubilization of heat-inactivated luciferase from insoluble aggregates.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: HSP104 is active in the cytosol, consistent with its role in disaggregating cytosolic protein aggregates. Confirmed by multiple localization studies. Reason: The cytosol is the primary compartment where HSP104 performs its disaggregation function. Consistent with IDA evidence at PMID:10467108 and NAS at PMID:20850366. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN007521008 · PANTHER:PTN007521008 SUPPORTS TRANSFER This fungal-node inference is seeded by S. cerevisiae HSP104 and agrees with its directly established cytosolic activity.
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: This obsolete unfolded-protein-binding IBA was inherited from an older PTHR11638 PAINT assertion, but GO:0051082 is absent from the current PAINT cache and from current GOA. PMID:16135516 still directly supports ATP-regulated unfolded-polypeptide binding by HSP104; migrate the retired row to HSP104's accepted ATP-dependent protein disaggregase activity rather than treating the true substrate-engagement claim as biologically false. Reason: GO:0051082 is retired, but retirement is not a biological REMOVE judgment. In HSP104, client binding is a mechanistic part of the ATP-dependent threading/disaggregation activity now captured by GO:0140545 and supported by direct disaggregation and translocation studies. Propagation Review Root cause: SOURCE STALE OR MISSING Sources checked: PANTHER:PTN007521008 · PANTHER:PTN007521008 SOURCE STALE OR MISSING The current PTHR11638 PAINT export no longer contains GO:0051082 on PTN007521008; the row is retained only as a retired historical GOA assertion. Proposed replacements: ATP-dependent protein disaggregase activity Supporting Evidence: PMID:16135516 the affinity of Hsp104 toward polypeptides is regulated by nucleotides. In the presence of ATP or adenosine-5' -O-(3-thiotriphosphate), the chaperone formed complexes with RCMLa, whereas no binding was observed in the presence of ADP.
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	Summary: HSP104 interacts directly with Hsp70 (Ssa1) and Hsp40 (Ydj1) chaperones as part of its disaggregation system. Also interacts with co-chaperones CNS1, CPR7, and STI1 (PMID:11604493). The species-specific interaction with the Hsp70 middle domain is essential for disaggregation (PMID:21474779). Reason: Chaperone binding is essential for HSP104 function. It requires cooperation with Hsp70/Hsp40 to disaggregate and refold substrates. PMID:9674429 directly demonstrates the physical and functional interaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN007521008 · PANTHER:PTN007521008 SUPPORTS TRANSFER The fungal-node assertion is seeded by S. cerevisiae HSP104 and agrees with direct functional interaction with Hsp70/Hsp40. Supporting Evidence: PMID:9674429 Hsp104 has a protein remodeling activity that acts on trapped, aggregated proteins and requires specific interactions with conventional chaperones to promote refolding of the intermediates it produces. PMID:21474779 the interaction between Hsp70/DnaK and helix 2 of the middle domain of Hsp104/ClpB determines the specificity required for protein disaggregation both in vivo and in vitro, as well as for cellular thermotolerance.
GO:0070370 cellular heat acclimation	IBA GO_REF:0000033	ACCEPT	Summary: HSP104 is the defining gene for induced thermotolerance in yeast. Deletion mutants fail to acquire thermotolerance after mild heat pretreatment (PMID:2188365). This is the original and best-established phenotype. Reason: Cellular heat acclimation (induced thermotolerance) is the core biological process for which HSP104 was originally identified. PMID:2188365: "when given a mild pre-heat treatment, the mutant cells did not acquire tolerance to heat, as did wild-type cells." Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN007521008 · PANTHER:PTN007521008 SUPPORTS TRANSFER The fungal node is grounded by Candida, S. pombe, and S. cerevisiae descendants; HSP104's own mutant phenotype directly establishes acquired thermotolerance. Supporting Evidence: PMID:2188365 when given a mild pre-heat treatment, the mutant cells did not acquire tolerance to heat, as did wild-type cells.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: Historical Swiss-Prot keyword IEA for nucleotide binding. HSP104 has two ATP-binding AAA+ domains, but this broad keyword row is absent from current GOA. Reason: The broad nucleotide-binding assertion is biologically true but stale as a GOA row; current GOA retains the more informative InterPro2GO ATP-binding row and direct ATP-binding/ADP-binding experimental rows.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: Historical UniProt combined-pipeline ATP-binding IEA. ATP binding is experimentally established for HSP104, but this GO_REF:0000120 row has been replaced in current GOA by an InterPro2GO ATP-binding row. Reason: Retired as a stale GOA source row rather than because the assertion is wrong; HSP104 ATP binding remains captured by active IEA and IMP annotations.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: HSP104 shuttles between cytoplasm and nucleus. Nuclear localization is confirmed by immunoelectron microscopy (PMID:10467108) and is enhanced under heat stress. IEA is consistent with IDA evidence. Reason: Confirmed by IDA at PMID:10467108. UniProt subcellular location mapping is accurate here, but the nuclear pool is stress-enhanced and secondary to HSP104's predominant cytosolic disaggregase function.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate of IBA and IDA annotations for cytoplasm. The IEA from UniProt subcellular location is consistent with experimental evidence. Reason: Consistent with IBA (GO_REF:0000033), IDA (PMID:10467108), and HDA (PMID:22842922) evidence for cytoplasmic localization.
GO:0005829 cytosol	IEA GO_REF:0000117	ACCEPT	Summary: Cytosol annotation by ARBA machine learning. Consistent with IBA and NAS annotations for the same term. Reason: Consistent with experimental and phylogenetic evidence.
GO:0006457 protein folding	IEA GO_REF:0000117	MODIFY	Summary: ARBA annotation for protein folding. HSP104 participates in the refolding of aggregated proteins in cooperation with Hsp70/Hsp40. More precisely, HSP104 participates in protein refolding (GO:0042026) rather than de novo protein folding. Reason: HSP104 does not participate in de novo protein folding. It specifically disaggregates and enables refolding of already-aggregated proteins. GO:0042026 "protein refolding" is the more precise term, consistent with the IDA annotation at PMID:9674429. Proposed replacements: protein refolding
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ATP hydrolysis activity from InterPro domain mapping. Fully consistent with IBA and IDA/IMP experimental evidence. Reason: Consistent with IBA (GO_REF:0000033), IDA (PMID:16135516), and IMP (PMID:16135516, PMID:9674429) evidence.
GO:0034605 cellular response to heat	IEA GO_REF:0000117	ACCEPT	Summary: ARBA annotation for cellular response to heat. HSP104 is massively induced by heat shock and plays a critical role in thermotolerance. Consistent with IDA at PMID:24291094. Reason: Consistent with direct experimental evidence (IDA at PMID:24291094) and the well-established role of HSP104 in heat stress response.
GO:0042802 identical protein binding	IEA GO_REF:0000117	ACCEPT	Summary: HSP104 forms a homohexamer, so identical protein binding is expected. Confirmed by cryoEM structure (PMID:20404203) and IPI evidence (PMID:20404203, PMID:21474779). Reason: HSP104 homohexamerization is well established. Consistent with IPI evidence.
GO:0043335 protein unfolding	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for protein unfolding by ARBA. Consistent with IBA and IMP (PMID:7984243) evidence. Reason: Consistent with IBA and IMP experimental evidence for protein unfolding as part of the disaggregation mechanism.
GO:0070013 intracellular organelle lumen	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA annotation placing HSP104 in intracellular organelle lumen. HSP104 is primarily cytosolic but has a stress-enhanced nuclear pool; because the true nuclear-lumen localization is captured by more informative nuclear/nuclear-periphery rows, this broad parent is not useful as a standalone compartment assertion. Reason: GO:0070013 is true through HSP104's curated nuclear localization but too broad beside the retained nucleus and nuclear-periphery annotations. Its placement would overstate the ER-lumen phenotype from PMID:10931304, which is likely mediated from the cytosolic side rather than by HSP104 residing in the ER lumen.
GO:0005515 protein binding	IPI PMID:16554755 Global landscape of protein complexes in the yeast Saccharom...	REMOVE	Summary: High-throughput TAP-tag study identifying global protein complexes in yeast. HSP104 was found to interact with multiple proteins including BLM10, COG6, CPR6, ECM2, EGH1, FCY1, HRD1, LAM6, LYS4, SGF73, SRB5, VPS4. Many of these are likely nonspecific interactions from the high-throughput screen. Reason: "Protein binding" (GO:0005515) is uninformative per GO curation guidelines. The underlying high-throughput TAP-tag interactions likely include both genuine and spurious associations, and this row is absent from current GOA. Supporting Evidence: PMID:16554755 We used tandem affinity purification to process 4,562 different tagged proteins of the yeast Saccharomyces cerevisiae.
GO:0005515 protein binding	IPI PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ...	REMOVE	Summary: Another high-throughput chaperone interaction study (TAP-tag based) mapping all 63 yeast chaperones' interaction networks. Again yields many interaction partners for HSP104. Reason: Same issue as above: "protein binding" is uninformative. While HSP104 clearly binds many proteins as a chaperone/disaggregase, the generic GO:0005515 term does not capture the mechanistic nature of these interactions. More informative rows already capture partner-chaperone binding and client processing, and this high-throughput IPI row is absent from current GOA. Supporting Evidence: PMID:19536198 Systematic analysis of physical TAP-tag based protein-protein interactions of all known 63 chaperones in Saccharomyces cerevisiae has been carried out.
GO:0005515 protein binding	IPI PMID:20850366 A chaperone cascade sorts proteins for posttranslational mem...	REMOVE	Summary: This study identified HSP104 as part of a chaperone cascade for tail-anchored (TA) protein targeting to the ER. The protein binding annotation with MDY2/Q12285 reflects the TRC complex interaction. Reason: While the interaction with the TRC complex is real and interesting, "protein binding" is uninformative. The specific biology (TRC complex membership) is already captured by GO:0072380. Supporting Evidence: PMID:20850366 we reveal the composition of a conserved multiprotein TMD recognition complex (TRC) and show that distinct TRC subunits recognize the two types of TMD signals.
GO:0042802 identical protein binding	IPI PMID:20404203 CryoEM structure of Hsp104 and its mechanistic implication f...	ACCEPT	Summary: CryoEM structure of the HSP104 hexamer confirms self-association. The hexameric ring structure is fundamental to HSP104 function. Reason: HSP104 homohexamerization is a core structural property essential for its disaggregase function. The cryoEM structure (PMID:20404203) provides direct structural evidence for self-association. This is more informative than generic "protein binding." Supporting Evidence: PMID:20404203 Hsp104 is a ring-forming AAA+ machine that recognizes both aggregated proteins and prion-fibrils as substrates and, together with the Hsp70 system, remodels substrates in an ATP-dependent manner.
GO:0042802 identical protein binding	IPI PMID:21474779 Species-specific collaboration of heat shock proteins (Hsp) ...	ACCEPT	Summary: Species-specificity study using Hsp104/ClpB chimeras confirms self-interaction properties. HSP104 hexamerization is well supported. Reason: Confirms HSP104 self-association. The study explicitly tests chimeric proteins in the context of disaggregation, showing that the middle domain determines specificity of interaction with Hsp70.
GO:0005829 cytosol	NAS PMID:20850366 A chaperone cascade sorts proteins for posttranslational mem...	ACCEPT	Summary: ComplexPortal annotation placing HSP104 in cytosol based on the TRC complex study. HSP104 cytosolic localization is well supported. Reason: Consistent with IBA and IDA evidence. Cytosol is the primary functional compartment.
GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane	NAS PMID:20850366 A chaperone cascade sorts proteins for posttranslational mem...	KEEP AS NON CORE	Summary: ComplexPortal annotation based on HSP104's role in the TRC complex for tail-anchored protein targeting. This is a secondary/moonlighting function, not the core disaggregase activity. Reason: PMID:20850366 shows HSP104 is part of a chaperone cascade for TA protein targeting to the ER membrane. This is a legitimate but non-core function. The primary function of HSP104 is protein disaggregation during heat stress, not TA protein targeting. Supporting Evidence: PMID:20850366 ER-bound TA proteins are sorted at the top of a TMD chaperone cascade that culminates with the formation of Get3-TA protein complexes, which are recruited to the ER membrane for insertion.
GO:0034605 cellular response to heat	IDA PMID:24291094 Coordination of translational control and protein homeostasi...	ACCEPT	Summary: Study demonstrating HSP104/Hsp70-dependent protein disaggregation drives disassembly of heat stress granules and restoration of translation during recovery. Direct evidence for HSP104's role in the cellular heat response. Reason: HSP104's role in heat stress response is its best-established biological function. PMID:24291094 provides direct evidence for HSP104 function in coordinating protein homeostasis and translational control during severe heat stress. Supporting Evidence: PMID:24291094 heat-SG disassembly and restoration of translation activity during heat stress recovery is intimately linked to disaggregation of damaged proteins present in the mixed assemblies and requires Hsp104 and Hsp70 activity.
GO:0016887 ATP hydrolysis activity	IDA PMID:16135516 Substrate binding to the molecular chaperone Hsp104 and its ...	ACCEPT	Summary: Direct biochemical demonstration of HSP104 ATPase activity and its regulation by substrate binding and nucleotide occupancy. Reason: PMID:16135516 provides direct in vitro assay evidence for ATP hydrolysis by HSP104, including characterization of how substrate binding commits the protein to ATP hydrolysis. Supporting Evidence: PMID:16135516 upon association with a polypeptide, a conformational change occurs within Hsp104 that strongly reduces the dynamics of nucleotide exchange and commits the bound polypeptide to ATP hydrolysis.
GO:0016887 ATP hydrolysis activity	IMP PMID:16135516 Substrate binding to the molecular chaperone Hsp104 and its ...	ACCEPT	Summary: Mutant phenotype evidence for ATP hydrolysis. Walker A (K218T) and Walker B (E285Q, E687Q) mutations abolish or dramatically reduce ATPase activity and impair substrate binding and disaggregation. Reason: Mutagenesis of key ATPase residues (K218T at NBD1, K620T at NBD2) demonstrates that ATP hydrolysis is required for HSP104 function. PMID:16135516 shows "When ATP binding to this domain was impaired by mutation, Hsp104 lost its ability to interact with RCMLa." Supporting Evidence: PMID:16135516 When ATP binding to this domain was impaired by mutation, Hsp104 lost its ability to interact with RCMLa.
GO:0016887 ATP hydrolysis activity	IMP PMID:9674429 Hsp104, Hsp70, and Hsp40: a novel chaperone system that resc...	ACCEPT	Summary: Mutant phenotype evidence from the landmark Glover & Lindquist (1998) paper establishing the Hsp104/Hsp70/Hsp40 disaggregation system. ATP hydrolysis is required for disaggregation activity. Reason: PMID:9674429 demonstrates that HSP104's protein remodeling activity is ATP-dependent and requires cooperation with Hsp70/Hsp40. Supporting Evidence: PMID:9674429 Hsp104 has a protein remodeling activity that acts on trapped, aggregated proteins and requires specific interactions with conventional chaperones to promote refolding of the intermediates it produces.
GO:0005737 cytoplasm	HDA PMID:22842922 Dissecting DNA damage response pathways by analysing protein...	ACCEPT	Summary: High-throughput microscopy study of GFP-tagged proteins under DNA replication stress. HSP104 localization to cytoplasm confirmed. Reason: Consistent with all other cytoplasm annotations. High-throughput direct assay evidence supports cytoplasmic localization. Supporting Evidence: PMID:22842922 Relocalization of proteins is a hallmark of the DNA damage response. We use high-throughput microscopic screening of the yeast GFP fusion collection
GO:0006457 protein folding	IDA PMID:9674429 Hsp104, Hsp70, and Hsp40: a novel chaperone system that resc...	MODIFY	Summary: PMID:9674429 demonstrates that HSP104 in concert with Hsp70/Hsp40 can reactivate aggregated proteins. This is more precisely "protein refolding" (GO:0042026) rather than general protein folding, since HSP104 acts on previously aggregated substrates, not nascent chains. Reason: HSP104 does not participate in de novo protein folding. It specifically disaggregates and enables refolding of already-aggregated proteins. GO:0042026 "protein refolding" is the more precise term. PMID:9674429: "Hsp104 can reactivate proteins that have been denatured and allowed to aggregate, substrates refractory to the action of other chaperones." Proposed replacements: protein refolding Supporting Evidence: PMID:9674429 Hsp104 can reactivate proteins that have been denatured and allowed to aggregate, substrates refractory to the action of other chaperones.
GO:0034399 nuclear periphery	IDA PMID:25817432 Cmr1/WDR76 defines a nuclear genotoxic stress body linking g...	KEEP AS NON CORE	Summary: PMID:25817432 identifies the intranuclear quality control compartment (INQ) where HSP104 colocalizes with Cmr1 and misfolded proteins at the nuclear periphery in response to genotoxic stress. Reason: PMID:25817432 provides direct evidence for HSP104 localization at the nuclear periphery as part of the INQ compartment, which sequesters misfolded proteins. This is consistent with HSP104's protein quality control function. Supporting Evidence: PMID:25817432 Cmr1--together with Mrc1/Claspin, Pph3, the chaperonin containing TCP1 (CCT) and 25 other proteins--define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress.
GO:0035617 cytoplasmic stress granule disassembly	IDA PMID:24291094 Coordination of translational control and protein homeostasi...	KEEP AS NON CORE	Summary: PMID:24291094 demonstrates that HSP104 is required for stress granule disassembly during recovery from severe heat stress. Heat-SGs coassemble with protein aggregates, and their disassembly is coupled to Hsp104-dependent protein disaggregation. Reason: This is a well-supported secondary function of HSP104. Stress granule disassembly is mechanistically linked to its core disaggregase activity. PMID:24291094 shows "heat-SG disassembly... requires Hsp104 and Hsp70 activity." Supporting Evidence: PMID:24291094 heat-SG disassembly and restoration of translation activity during heat stress recovery is intimately linked to disaggregation of damaged proteins present in the mixed assemblies and requires Hsp104 and Hsp70 activity.
GO:0005524 ATP binding	IMP PMID:11867765 Analysis of the AAA sensor-2 motif in the C-terminal ATPase ...	ACCEPT	Summary: Mutagenesis study of the AAA sensor-2 motif in NBD2. R826M mutation decreases ATP and ADP affinity at NBD2, confirming nucleotide binding properties. Fluorescence probe (Y819W) directly measures ATP/ADP binding at NBD2. Reason: PMID:11867765 provides direct evidence for ATP binding through mutagenesis of the sensor-2 motif, confirming the importance of NBD2 nucleotide binding for HSP104 function. Supporting Evidence: PMID:11867765 The fluorescence of this tryptophan changes in response to ATP and ADP binding, allowing the K(d) and Hill coefficient to be determined for each nucleotide.
GO:0005634 nucleus	IDA PMID:10467108 Direct evidence for the intracellular localization of Hsp104...	KEEP AS NON CORE	Summary: Immunoelectron microscopy demonstrating HSP104 presence in the nucleus. Nuclear accumulation is enhanced by heat shock. Reason: Direct immunoEM evidence for nuclear localization. PMID:10467108: "a small amount of Hsp104 was located in the cytoplasm and nucleus." This is consistent with HSP104's role in nuclear protein quality control (INQ compartment). Supporting Evidence: PMID:10467108 At normal temperature (25 degrees C), a small amount of Hsp104 was located in the cytoplasm and nucleus.
GO:0005737 cytoplasm	IDA PMID:10467108 Direct evidence for the intracellular localization of Hsp104...	ACCEPT	Summary: Same immunoelectron microscopy study confirming cytoplasmic localization. HSP104 concentrates around protein aggregates in the cytoplasm during heat shock. Reason: Direct evidence. PMID:10467108: "Hsp104 increased around the aggregates with increasing time of the mild heat-shock treatment." Supporting Evidence: PMID:10467108 On exposure to mild heat-shock at 40 degrees C, protein aggregates appeared in the cytoplasm and nucleus, and Hsp104 increased around the aggregates with increasing time of the mild heat-shock treatment.
GO:0005991 trehalose metabolic process	IMP PMID:9797333 Evidence for the interplay between trehalose metabolism and ...	MARK AS OVER ANNOTATED	Summary: PMID:9797333 shows that HSP104 disruption affects trehalose metabolism: activities of trehalose-synthesizing and -hydrolyzing enzymes are reduced in hsp104 mutants during heat shock. However, this is likely an indirect effect of impaired protein quality control, not a direct role in trehalose metabolism. Reason: The effect on trehalose metabolism is likely indirect. HSP104's disaggregase activity may be needed to maintain the functional integrity of trehalose metabolic enzymes during heat stress, rather than HSP104 directly participating in trehalose metabolism. PMID:9797333: "The activities of trehalose-synthesizing and -hydrolyzing enzymes are low in the HSP104 disruption mutant during heat shock." This is consistent with a general protein quality control defect rather than a direct metabolic role. Supporting Evidence: PMID:9797333 The activities of trehalose-synthesizing and -hydrolyzing enzymes are low in the HSP104 disruption mutant during heat shock.
GO:0034975 protein folding in endoplasmic reticulum	IMP PMID:10931304 Trehalose is required for conformational repair of heat-dena...	KEEP AS NON CORE	Summary: PMID:10931304 shows that HSP104 is required for conformational repair of heat-denatured proteins in the ER. However, HSP104 is a cytosolic protein and likely acts indirectly on ER protein folding, possibly through effects on the cytosolic face of the ER or through indirect signaling. Reason: While the genetic evidence is clear that HSP104 affects ER protein folding after heat stress, the mechanism is indirect since HSP104 is cytosolic. PMID:10931304: "not only ER chaperones but also the cytosolic Hsp104 chaperone is required for conformational repair events in the ER lumen." This is a non-core function and the mechanism may involve maintaining cytosolic factors needed for ER homeostasis. Supporting Evidence: PMID:10931304 not only ER chaperones but also the cytosolic Hsp104 chaperone is required for conformational repair events in the ER lumen.
GO:0043335 protein unfolding	IMP PMID:7984243 Protein disaggregation mediated by heat-shock protein Hsp104...	ACCEPT	Summary: The landmark Parsell et al. (1994) paper demonstrating that HSP104 mediates resolubilization of heat-inactivated protein aggregates. The "protein unfolding" annotation captures the mechanical unfolding of aggregated polypeptides during the threading/disaggregation process. Reason: PMID:7984243 establishes HSP104's unique protein disaggregation function, which mechanistically involves unfolding aggregated proteins. This is a core aspect of HSP104 function. Supporting Evidence: PMID:7984243 Hsp104 functions in a manner not previously described for other heat-shock proteins: it mediates the resolubilization of heat-inactivated luciferase from insoluble aggregates.
GO:0043531 ADP binding	IMP PMID:11867765 Analysis of the AAA sensor-2 motif in the C-terminal ATPase ...	ACCEPT	Summary: PMID:11867765 uses a site-specific fluorescent probe (Y819W) to measure both ATP and ADP binding at NBD2, confirming ADP binding with defined affinity. Reason: ADP binding at NBD2 is important for HSP104 hexamer stabilization and allosteric regulation. PMID:11867765 directly measures ADP binding affinity using fluorescence changes. Supporting Evidence: PMID:11867765 The fluorescence of this tryptophan changes in response to ATP and ADP binding, allowing the K(d) and Hill coefficient to be determined for each nucleotide.
GO:0051082 unfolded protein binding	IDA PMID:16135516 Substrate binding to the molecular chaperone Hsp104 and its ...	MODIFY	Summary: PMID:16135516 directly demonstrates ATP-dependent binding of HSP104 to RCMLa, a permanently unfolded model substrate. This supports the binding claim represented by the original annotation, but GO:0051082 is now obsolete and the row is absent from current GOA. Reason: GO:0051082 is retired, but the cited nucleotide-regulated substrate-binding assay supports HSP104 client engagement rather than a false molecular-function claim. In HSP104, that engagement is part of the accepted ATP-dependent protein disaggregase activity, making GO:0140545 the best replacement. Proposed replacements: ATP-dependent protein disaggregase activity Supporting Evidence: PMID:16135516 the affinity of Hsp104 toward polypeptides is regulated by nucleotides. In the presence of ATP or adenosine-5' -O-(3-thiotriphosphate), the chaperone formed complexes with RCMLa, whereas no binding was observed in the presence of ADP.
GO:0051087 protein-folding chaperone binding	IDA PMID:9674429 Hsp104, Hsp70, and Hsp40: a novel chaperone system that resc...	ACCEPT	Summary: PMID:9674429 demonstrates direct functional cooperation between HSP104 and Hsp70/Hsp40 chaperones. HSP104 requires these partner chaperones for effective disaggregation and refolding. Reason: Physical and functional interaction with Hsp70 (Ssa1) and Hsp40 (Ydj1) is essential for HSP104 disaggregase function. PMID:9674429 is the definitive study establishing the Hsp104/Hsp70/Hsp40 chaperone system. Supporting Evidence: PMID:9674429 Hsp104 has a protein remodeling activity that acts on trapped, aggregated proteins and requires specific interactions with conventional chaperones to promote refolding of the intermediates it produces.
GO:0070370 cellular heat acclimation	IMP PMID:2188365 HSP104 required for induced thermotolerance.	ACCEPT	Summary: The foundational paper showing HSP104 is required for induced thermotolerance. hsp104 deletion mutants fail to acquire heat tolerance after mild preconditioning. Reason: This is the original and defining functional study for HSP104. PMID:2188365: "when given a mild pre-heat treatment, the mutant cells did not acquire tolerance to heat, as did wild-type cells." Supporting Evidence: PMID:2188365 when given a mild pre-heat treatment, the mutant cells did not acquire tolerance to heat, as did wild-type cells. Transformation with the wild-type gene rescued the defect of mutant cells.
GO:0072380 TRC complex	IDA PMID:20850366 A chaperone cascade sorts proteins for posttranslational mem...	KEEP AS NON CORE	Summary: PMID:20850366 identifies HSP104 as a component of the TMD recognition complex (TRC), involved in sorting tail-anchored proteins for ER membrane insertion. This is a secondary/moonlighting function for HSP104. Reason: The TRC complex role is a legitimate but non-core function of HSP104. Its primary role is as a protein disaggregase. The TRC complex function represents a specialized use of HSP104's chaperone capabilities in TA protein biogenesis. Supporting Evidence: PMID:20850366 we reveal the composition of a conserved multiprotein TMD recognition complex (TRC) and show that distinct TRC subunits recognize the two types of TMD signals.
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO infers ATP binding from the AAA+ NBD signatures in HSP104. HSP104 has two ATP-binding AAA+ domains and the assignment agrees with direct NBD2 nucleotide-binding evidence. Reason: This is a correct domain-based ATP-binding assignment and replaces the older stale GO_REF:0000120 ATP-binding IEA. PMID:11867765 experimentally shows ATP and ADP binding at NBD2. Supporting Evidence: PMID:11867765 The fluorescence of this tryptophan changes in response to ATP and ADP binding, allowing the K(d) and Hill coefficient to be determined for each nucleotide.
GO:0015450 protein-transporting ATPase activity	IDA PMID:31027887 Hsp104 and Potentiated Variants Can Operate as Distinct Nonp...	REMOVE	Summary: PMID:31027887 assays ATP-dependent movement of soluble polypeptides through the HSP104 axial pore, not primary active movement of a protein substrate across a membrane. Reason: GO:0015450 is a transmembrane protein-transporter term. Although HSP104 can act as an ATP-dependent axial-pore translocase on soluble polypeptides, the cited kinetic assay does not support carrier-mediated protein transport across a membrane. Supporting Evidence: PMID:31027887 We establish that Hsp104 and Hsp104 A503S can operate as nonprocessive translocases for soluble substrates
GO:0071806 protein transmembrane transport	IEA GO_REF:0000108	REMOVE	Summary: This logical-inference row is derived from the unsupported GO:0015450 transmembrane protein-transporter assertion. Reason: HSP104 threads soluble polypeptide substrates through its cytosolic AAA+ pore during disaggregation, but it does not mediate transmembrane protein transport. The GO_REF:0000108 inference should fall with the inappropriate GO:0015450 source assertion.
GO:0072380 TRC complex	NAS PMID:20850366 A chaperone cascade sorts proteins for posttranslational mem...	KEEP AS NON CORE	Summary: ComplexPortal propagates HSP104 as a TRC-complex component from the same Schuldiner et al. tail-anchored protein-targeting study that supports the SGD IDA TRC row. Reason: The TRC complex role is a plausible specialized, non-core deployment of HSP104's chaperone capacity in the GET/TA protein-targeting pathway, matching the older SGD direct annotation to GO:0072380. Supporting Evidence: PMID:20850366 we reveal the composition of a conserved multiprotein TMD recognition complex (TRC) and show that distinct TRC subunits recognize the two types of TMD signals.
GO:0140545 ATP-dependent protein disaggregase activity	IDA PMID:31027887 Hsp104 and Potentiated Variants Can Operate as Distinct Nonp...	ACCEPT	Summary: The new SGD IDA row captures HSP104's defining ATP-dependent disaggregase activity. PMID:31027887 demonstrates ATP-dependent soluble-polypeptide translocation; earlier direct work established aggregate resolubilization, Hsp70/Hsp40-dependent reactivation, and substrate threading. Reason: GO:0140545 is the correct specific molecular function for HSP104. PMID:31027887 supplies the current SGD direct evidence for ATP-dependent polypeptide translocation, and the older direct disaggregation and threading studies establish that this axial-pore ATPase activity is used to solubilize ordered protein aggregates. Supporting Evidence: PMID:31027887 Hsp104 couples the energy of ATP binding and hydrolysis to solubilize proteins trapped in aggregated structures. PMID:7984243 Hsp104 functions in a manner not previously described for other heat-shock proteins: it mediates the resolubilization of heat-inactivated luciferase from insoluble aggregates. PMID:9674429 in concert with Hsp40 and Hsp70, Hsp104 can reactivate proteins that have been denatured and allowed to aggregate, substrates refractory to the action of other chaperones. PMID:18312264 HAP variants that harbour a reduced threading activity were affected in both protein disaggregation and prion propagation, demonstrating that substrate threading represents the common mechanism for the processing of both substrate classes.

Gene Description

Existing Annotations Review

Core Functions

HSP104 physically and functionally cooperates with Hsp70/Hsp40 chaperones, which are required for substrate delivery and downstream refolding.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

SGD

SGD gene description for HSP104 (yeast)

📚 Additional Documentation

Notes

Bioreason Rl Predictions

Bioreason Rl Review

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