LHS1 encodes a Grp170/Hsp110-like Hsp70-family chaperone of the endoplasmic reticulum lumen. Lhs1p cooperates with Kar2/BiP during ER protein biogenesis as a Kar2 nucleotide exchange factor, functions as a client holdase, supports efficient translocation and folding of secretory and ER client proteins, and helps select a subset of misfolded membrane proteins for Hrd1-dependent ER-associated degradation.
Definition: Binding to an unfolded or misfolded protein to prevent its aggregation without actively catalyzing refolding. The holdase maintains the client protein in a soluble, folding-competent state. This is mechanistically distinct from foldase activity (GO:0044183) and from carrier-holdase activity (GO:0140309).
Justification: Lhs1p's direct Kar2 nucleotide-exchange activity is nucleotide-dependent, but purified Lhs1p can suppress luciferase aggregation independently of nucleotide binding. Obsolete GO:0051082 captured binding only; GO:0044183 requires assisting folding, and GO:0140309 keeps a carrier-specific definition requiring escort to an acceptor molecule or location. See go-ontology#30552. The proposed parent is the molecular_function root because GO has no general chaperone-activity grouping term; GO:0044183 protein folding chaperone is itself a direct child of GO:0003674.
Parent term: molecular_function
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000774 adenyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Lhs1p has nucleotide exchange factor activity for Kar2/BiP. Reason: Lhs1p stimulates nucleotide exchange on Kar2 and this activity is required for ER protein biogenesis. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002900795 · PANTHER:PTN002900795 SUPPORTS TRANSFER The current PTHR45639 PAINT tree places this term at the Hsp110/Grp170/Lhs1 node. LHS1's self-seed SGD:S000001556 records direct descendant evidence for Lhs1p and is not circular. |
| GO:0034663 endoplasmic reticulum chaperone complex | IBA GO_REF:0000033 | ACCEPT | Summary: Lhs1p functions in the ER chaperone system with Kar2. Reason: The ER chaperone-complex annotation captures LHS1's role in the luminal Hsp70/Kar2 folding and translocation system. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000452651 · PANTHER:PTN000452651 SUPPORTS TRANSFER The current PTHR45639 PAINT tree places this term at the eukaryotic Grp170 node, whose ER chaperone-system activity is conserved in yeast Lhs1p. |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: The broad keyword nucleotide-binding row is no longer in current GOA. Reason: Lhs1p nucleotide binding is real and necessary for NEF activity, but the current ATP-binding and NEF rows capture the same biology more specifically than this retired UniProt keyword assertion. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: This exact GO_REF:0000120 ATP-binding row is no longer in current GOA. Reason: Direct nucleotide-binding studies support ATP binding by Lhs1p, even though canonical ATP hydrolysis is limited compared with Hsp70s. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell mapping of the manually curated ER-lumen localization of Lhs1p. Reason: Lhs1p is an ER-lumenal Grp170-family chaperone whose NEF and holdase functions act on ER-lumenal clients and on Kar2/BiP in the ER lumen; the current UniProt entry records this compartment directly. Supporting Evidence: file:yeast/LHS1/LHS1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: Broad hydrolase activity is less informative than ATP binding/ATP hydrolysis/chaperone terms. Reason: Lhs1p belongs to the Hsp70 family and has nucleotide-dependent chaperone biology, but generic hydrolase activity is too broad to represent the curated function. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000120 | ACCEPT | Summary: Manual review: ATP hydrolysis activity is consistent with known biology of LHS1. Reason: Lhs1p has Kar2-stimulated ATPase activity; PMID:14704430 reports reciprocal activation of the Lhs1p ATPase by Kar2p. |
| GO:0005515 protein binding | IPI PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ... | REMOVE | Summary: Generic protein binding does not capture LHS1's specific chaperone role. Reason: This retired IntAct row came from a high-throughput TAP/MS chaperone interactome. The paper reports indirect copurification rather than a specific Lhs1p molecular activity, and generic protein binding should not be kept when NEF and holdase/chaperone terms capture the direct functions. 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:23217712 CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abund... | REMOVE | Summary: Manual review: protein binding is too generic or over-extended for LHS1. Reason: This stale IntAct row is no longer in current UniProt or GOA and points to a cytosolic Ssa1 cell-cycle phosphoregulation study, not to a distinct Lhs1p molecular function. Generic protein binding should not be retained for Lhs1p's specific ER NEF and holdase biology. |
| GO:0005783 endoplasmic reticulum | HDA PMID:26928762 One library to make them all: streamlining the creation of y... | KEEP AS NON CORE | Summary: High-throughput tagging evidence is consistent with ER localization, but is less precise than the ER lumen annotations. Reason: The core localization is endoplasmic reticulum lumen; the broader ER annotation is correct but redundant and less specific. |
| GO:0000774 adenyl-nucleotide exchange factor activity | IDA PMID:14704430 Coordinated activation of Hsp70 chaperones. | ACCEPT | Summary: Direct assay evidence supports Lhs1p NEF activity for Kar2. Reason: Lhs1p provides specific nucleotide exchange activity for Kar2 and this activity is vital for ER protein biogenesis. Supporting Evidence: PMID:14704430 Lhs1p stimulated Kar2p by providing a specific nucleotide exchange activity, whereas Kar2p reciprocally activated the Lhs1p adenosine triphosphatase (ATPase). PMID:19759005 Lhs1p-dependent nucleotide exchange activity is vital for ER protein biogenesis file:yeast/LHS1/LHS1-deep-research-falcon.md Lhs1 is grouped with Hsp110-like proteins and described as acting as a NEF for Kar2 |
| GO:0005524 ATP binding | IDA PMID:19759005 Nucleotide binding by Lhs1p is essential for its nucleotide ... | ACCEPT | Summary: Direct nucleotide-binding evidence supports ATP binding by Lhs1p. Reason: Lhs1p's nucleotide-binding domain binds ATP and nucleotide binding is required for NEF function in vivo. Supporting Evidence: PMID:19759005 GdnHCl-EDTA-treated Lhs1p exhibits efficient nucleotide binding activity. |
| GO:0005524 ATP binding | IMP PMID:19759005 Nucleotide binding by Lhs1p is essential for its nucleotide ... | ACCEPT | Summary: Mutant phenotype evidence supports the importance of Lhs1p ATP/nucleotide binding. Reason: Nucleotide-binding mutations impair Lhs1p function in vivo, showing the ATP/nucleotide-binding state is functionally required. Supporting Evidence: PMID:19759005 nucleotide binding to Lhs1p is essential for its role in protein translocation |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:8654361 A novel Hsp70 of the yeast ER lumen is required for the effi... | ACCEPT | Summary: Lhs1p is a luminal ER Hsp70-family chaperone. Reason: LHS1 was identified as a lumenal Hsp70 of the ER, consistent with its secretory-protein translocation/folding role. Supporting Evidence: PMID:8654361 We therefore propose to designate this gene LHS1 (Lumenal Hsp Seventy). |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:8887673 SSI1 encodes a novel Hsp70 of the Saccharomyces cerevisiae e... | ACCEPT | Summary: Baxter et al. directly confirmed the ER localization of Ssi1p/Lhs1p by subcellular fractionation, protease protection, and immunofluorescence. Reason: This IDA row is the direct experimental basis for assigning Lhs1p to the ER lumen, its site of action in protein translocation, folding, and ER quality control. Supporting Evidence: PMID:8887673 The localization of Ssi1p to the ER, suggested by the presence of a conserved S. cerevisiae ER retention signal at its C terminus, was confirmed by subcellular fractionation, protease protection assays, and immunofluorescence. |
| GO:0006986 response to unfolded protein | IMP PMID:8654361 A novel Hsp70 of the yeast ER lumen is required for the effi... | ACCEPT | Summary: Loss of LHS1 activates the unfolded protein response. Reason: Lhs1p loss produces ER folding/translocation stress and depends on UPR activation for tolerance. Supporting Evidence: PMID:8654361 LHS1 is regulated by the unfolded protein response pathway. |
| GO:0006986 response to unfolded protein | IMP PMID:8887673 SSI1 encodes a novel Hsp70 of the Saccharomyces cerevisiae e... | ACCEPT | Summary: Baxter et al. showed that SSI1/LHS1 is induced by tunicamycin and in a kar2-159 mutant background, two conditions that accumulate unfolded proteins in the ER. Reason: The induction of SSI1/LHS1 under ER unfolded-protein stress supports its role in the unfolded protein response network, consistent with the independent LHS1 disruption phenotype from PMID:8654361. Supporting Evidence: PMID:8887673 Like KAR2, SSI1 is induced both in the presence of tunicamycin and in a kar2-159 mutant strain, conditions which lead to an accumulation of unfolded proteins in the ER. |
| GO:0031204 post-translational protein targeting to membrane, translocation | IMP PMID:8654361 A novel Hsp70 of the yeast ER lumen is required for the effi... | ACCEPT | Summary: LHS1 supports protein translocation into the ER. Reason: Lhs1p loss causes translocation defects for multiple secretory preproteins. Supporting Evidence: PMID:8654361 The Lhs1 null mutant exhibits a severe constitutive defect in the translocation of several secretory preproteins. |
| GO:0031204 post-translational protein targeting to membrane, translocation | IMP PMID:8887673 SSI1 encodes a novel Hsp70 of the Saccharomyces cerevisiae e... | ACCEPT | Summary: Baxter et al. found that SSI1/LHS1 deletion partially blocks the ER translocation of multiple proteins. Reason: The ssi1/lhs1 deletion phenotype directly supports an Lhs1p contribution to post-translational protein translocation into the ER and corroborates the independent translocation phenotype in the LHS1 null mutant from PMID:8654361. Supporting Evidence: PMID:8887673 SSI1 deletion strains show a partial block in translocation of multiple proteins into the ER, suggesting that Ssi1p plays a direct role in the translocation process. |
| GO:0051082 unfolded protein binding | IMP PMID:10409721 Cer1p functions as a molecular chaperone in the endoplasmic ... | MODIFY | Summary: The retired unfolded-protein-binding row reflects Lhs1p holdase/client chaperone activity rather than ATP-dependent foldase activity. Reason: This old GO:0051082 row is no longer in current GOA. The cited pro-CPY/peptide interaction paper supports direct holdase-like client engagement, but GO lacks a general in-situ holdase molecular-function term for Lhs1p. Proposed replacements: holdase chaperone activity |
| GO:0051082 unfolded protein binding | IMP PMID:8654361 A novel Hsp70 of the yeast ER lumen is required for the effi... | MODIFY | Summary: This unfolded-protein-binding row is no longer in current GOA. Reason: Defer to the SGD curator's full-text assessment of the original IMP annotation, but the accessible abstract supports ER lumen localization, UPR induction, and translocation/folding phenotypes rather than conversion to an ATP-dependent foldase term. Proposed replacements: holdase chaperone activity |
| GO:0051082 unfolded protein binding | IMP PMID:8887673 SSI1 encodes a novel Hsp70 of the Saccharomyces cerevisiae e... | MODIFY | Summary: This unfolded-protein-binding row is no longer in current GOA. Reason: Defer to the SGD curator's full-text assessment of the original IMP annotation, but the accessible abstract supports ER localization, Kar2 genetic interaction, UPR induction, and translocation phenotypes rather than conversion to an ATP-dependent foldase term. Proposed replacements: holdase chaperone activity |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro2GO ATP-binding assertion is consistent with direct ATP-binding evidence for Lhs1p. Reason: Lhs1p has a conserved Hsp70 nucleotide-binding domain and directly binds ATP in vitro; this current InterPro2GO row replaces the older combined-method ATP-binding source tuple. |
| GO:0036503 ERAD pathway | IMP PMID:37702403 Lhs1 dependent ERAD is determined by transmembrane domain co... | NEW | Summary: Lhs1p selects a subset of misfolded membrane substrates for ERAD with the Hrd1/Sec61 machinery. Reason: Lhs1p itself performs substrate-selection work for unglycosylated two-pass membrane ERAD substrates with orphaned or unassembled transmembrane domains, so ERAD captures a direct chaperone role rather than a downstream phenotype. Supporting Evidence: PMID:23645669 These data establish the first evidence that Lhs1/Grp170 chaperones can act as mediators of ERAD substrate selection. PMID:37702403 TMD characteristics and inter-domain contacts dictate whether Lhs1 is required for the selection of a given substrate for ERAD. |
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Download this section (compressed HTML)Q: Should GO annotations separate Lhs1p's Kar2 NEF role from its independent holdase/chaperone activity with additional experimental qualifiers?
Experiment: Compare LHS1 nucleotide-binding mutants and holdase-defective mutants in matched ER translocation and client-folding assays to separate NEF and direct chaperone functions.
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Download this section (compressed HTML)Molecular chaperone of the endoplasmic reticulum lumen; involved in polypeptide translocation and folding; nucleotide exchange factor for the ER lumenal Hsp70 chaperone Kar2p; regulated by the unfolded protein response pathway
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