LHS1

UniProt ID: P36016
Organism: Saccharomyces cerevisiae
Review Status: COMPLETE
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Gene Description

LHS1 encodes a Grp170/Hsp110-like Hsp70-family chaperone of the endoplasmic reticulum lumen. Lhs1p cooperates with Kar2/BiP during ER protein biogenesis: it acts as a nucleotide exchange factor for Kar2, contributes holdase/chaperone activity, and supports efficient translocation and folding of secretory and ER client proteins.

Existing Annotations Review

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.
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.
GO:0000166 nucleotide binding
IEA
GO_REF:0000043 		ACCEPT
Summary: Lhs1p nucleotide binding is necessary for NEF activity.
Reason: Nucleotide binding drives Lhs1p conformation and is essential for its Kar2 nucleotide-exchange activity.
GO:0005524 ATP binding
IEA
GO_REF:0000120 		ACCEPT
Summary: Lhs1p binds ATP as part of its divergent Hsp70 nucleotide-binding cycle.
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: Manual review: endoplasmic reticulum lumen is consistent with known biology of LHS1.
Reason: Retained as supported or plausible for this gene and evidence context.
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 ... 		MARK AS OVER ANNOTATED
Summary: Generic protein binding does not capture LHS1's specific chaperone role.
Reason: The more informative annotation is Lhs1p's ER chaperone/NEF function with Kar2 and client proteins.
GO:0005515 protein binding
IPI
PMID:23217712
CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abund... 		MARK AS OVER ANNOTATED
Summary: Manual review: protein binding is too generic or over-extended for LHS1.
Reason: Marked over-annotated because more specific terms capture the biology more accurately.
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
Falcon literature synthesis supports LHS1 as an ER-luminal Hsp70-family NEF and chaperone.
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: Manual review: endoplasmic reticulum lumen is consistent with known biology of LHS1.
Reason: Retained as supported or plausible for this gene and evidence context.
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: Manual review: response to unfolded protein is consistent with known biology of LHS1.
Reason: Retained as supported or plausible for this gene and evidence context.
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: Manual review: post-translational protein targeting to membrane, translocation is consistent with known biology of LHS1.
Reason: Retained as supported or plausible for this gene and evidence context.
GO:0051082 unfolded protein binding
IMP
PMID:10409721
Cer1p functions as a molecular chaperone in the endoplasmic ... 		MODIFY
Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for LHS1.
Reason: Lhs1p acts as an ER protein-folding chaperone and holdase; generic unfolded protein binding should be replaced by ATP-dependent protein folding chaperone.
GO:0051082 unfolded protein binding
IMP
PMID:8654361
A novel Hsp70 of the yeast ER lumen is required for the effi... 		MODIFY
Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for LHS1.
Reason: Lhs1p is an ER-luminal Hsp70-family chaperone; ATP-dependent protein folding chaperone is more specific than generic unfolded protein binding.
GO:0051082 unfolded protein binding
IMP
PMID:8887673
SSI1 encodes a novel Hsp70 of the Saccharomyces cerevisiae e... 		MODIFY
Summary: Manual review: unfolded protein binding is better represented by a more specific replacement term for LHS1.
Reason: The evidence concerns ER chaperone function in folding/translocation, not nonspecific binding to unfolded proteins.

Core Functions

Lhs1p is a Grp170/Lhs1p-subfamily Hsp70 that stimulates nucleotide exchange on Kar2/BiP, coordinating the ER luminal chaperone cycle required for protein translocation and folding.

Molecular Function:
adenyl-nucleotide exchange factor activity
Directly Involved In:
post-translational protein targeting to membrane, translocation response to unfolded protein
Cellular Locations:
endoplasmic reticulum lumen
In Complex:
endoplasmic reticulum chaperone complex
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
    Falcon literature synthesis supports LHS1 as an ER-luminal Kar2 nucleotide exchange factor and chaperone.

Lhs1p also has direct chaperone/holdase activity in the ER lumen, supporting folding and translocation of secretory-pathway client proteins.

Molecular Function:
ATP-dependent protein folding chaperone
Directly Involved In:
post-translational protein targeting to membrane, translocation
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • PMID:10409721
    Together, this suggests that Cer1p has a chaperoning activity required for proper refolding of denatured pro-CPY which is mediated by direct interaction with the unfolded polypeptide.
  • PMID:8654361
    We therefore propose that Lhs1p is a molecular chaperone of the ER lumen involved in both polypeptide translocation and subsequent protein folding.
  • file:interpro/panther/PTHR45639/PTHR45639-metadata.yaml
    PANTHER PTHR45639 provides Hsp70/Hsp110-family context for LHS1.

References

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Suggested Questions for Experts

Q: Should GO annotations separate Lhs1p's Kar2 NEF role from its independent holdase/chaperone activity with additional experimental qualifiers?

Suggested Experiments

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.

Deep Research

Falcon

(LHS1-deep-research-falcon.md)

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