STIP1

UniProt ID: P31948
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

STIP1 (stress-induced phosphoprotein 1), better known as HOP (Hsp70-Hsp90 organizing protein) or p60, is a cytoplasmic (and partly nuclear) TPR-domain adaptor co-chaperone. It contains three TPR (tetratricopeptide repeat) domains. The TPR1 domain binds the C-terminal EEVD motif of HSP70 (HSPA8/HSC70), while the TPR2A and TPR2B domains bind the C-terminal MEEVD motif of HSP90. By simultaneously engaging both chaperones, HOP physically bridges the HSP70 and HSP90 systems and coordinates the transfer of client proteins from HSP70 to HSP90 during the chaperone cycle. HOP has no catalytic activity; it functions as a scaffold/adaptor that modulates HSP90 conformation and client maturation. It is a defining component of the HSP70-HSP90 multichaperone machine and participates in the maturation of diverse clients including protein kinases and steroid hormone receptors.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0051879 Hsp90 protein binding
IBA
GO_REF:0000033 		ACCEPT
Summary: HOP binds HSP90 directly via its TPR2A/TPR2B domains (HSP90 C-terminal MEEVD). This is a core molecular function.
Reason: Directly supported by UniProt FUNCTION/DOMAIN and by experimental HSP90 interaction data; HSP90 binding is central to HOP's adaptor role.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
The TPR 4, 5 and 6 repeats (also called TPR2A domain) and TPR 7, 8 and 9 repeats (also called TPR2B domain) interact with HSP90.
GO:0005634 nucleus
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: HOP is detected in the nucleus in addition to the cytoplasm; nuclear shuttling is documented.
Reason: UniProt lists Nucleus as a subcellular location; nuclear pool is real but HOP's principal chaperone-organizing function is cytoplasmic.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: HOP is predominantly cytoplasmic, where it organizes the HSP70-HSP90 machine.
Reason: Matches UniProt subcellular location; cytoplasm is the genuine principal compartment of HOP.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0120293 dynein axonemal particle
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: By-similarity localization to the dynein axonemal particle, reflecting a role of HOP/co-chaperones in cytoplasmic preassembly of axonemal dynein in ciliated cells.
Reason: Specialized, by-similarity localization in ciliated-cell contexts; peripheral to HOP's general cytoplasmic chaperone-organizing function.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Dynein axonemal particle
GO:0005515 protein binding
IPI
PMID:20029029
Regulation of epidermal growth factor receptor trafficking b... 		KEEP AS NON CORE
Summary: Interaction with EGFR (P00533), an HSP90 client kinase. Bare protein binding is uninformative; the interaction is consistent with HOP's role in client maturation but is a generic binding term.
Reason: Records a real interaction with an HSP90 client (EGFR), but bare protein binding is uninformative and not elevated to core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifi... 		KEEP AS NON CORE
Summary: High-throughput interaction (partner Q96AP0). Bare protein binding is uninformative and the partner is not part of HOP's core chaperone function.
Reason: Records a real interaction but bare protein binding is uninformative; not core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:21170051
Mixed Hsp90-cochaperone complexes are important for the prog... 		MODIFY
Summary: Interaction with HSP90AB1 (P08238). Bare protein binding is uninformative; this HSP90 interaction is better captured as Hsp90 protein binding.
Reason: The WITH partner is HSP90AB1 (P08238); the interaction is precisely captured as Hsp90 protein binding, a core HOP function.
Proposed replacements: Hsp90 protein binding
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:21360678
Label-free quantitative proteomics and SAINT analysis enable... 		KEEP AS NON CORE
Summary: Interaction with PPP5C (P53041), a TPR-domain HSP90 co-chaperone phosphatase. Bare protein binding is uninformative; the partner is chaperone-machinery-related.
Reason: Real interaction with a co-chaperone (PPP5C) within the HSP90 machine, but bare protein binding is uninformative; not elevated to core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:25036637
A quantitative chaperone interaction network reveals the arc... 		MODIFY
Summary: Quantitative chaperone interaction network capturing HOP with HSP90AB1 (P08238) and CDC37L1 (Q7L3B6) among others. Bare protein binding is uninformative; the meaningful partner is HSP90.
Reason: WITH partners include HSP90AB1 (P08238); the chaperone-network interaction is precisely captured as Hsp90 protein binding.
Proposed replacements: Hsp90 protein binding
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:28330616
Systematic Analysis of Human Protein Phosphatase Interaction... 		KEEP AS NON CORE
Summary: Interaction with PPP5C (P53041), an HSP90 co-chaperone. Bare protein binding is uninformative.
Reason: Real interaction with a chaperone-machinery component but uninformative protein binding term; not core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		MODIFY
Summary: Binary interactome capturing HOP with HSP90AB1 (P08238) and another partner. Bare protein binding is uninformative; the meaningful partner is HSP90.
Reason: WITH partner HSP90AB1 (P08238); precisely captured as Hsp90 protein binding.
Proposed replacements: Hsp90 protein binding
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:31980649
Extensive rewiring of the EGFR network in colorectal cancer ... 		KEEP AS NON CORE
Summary: Interaction with EGFR (P00533) and ERBB2 (P04626), HSP90 client kinases. Bare protein binding is uninformative; consistent with HOP's client-maturation role.
Reason: Records real interactions with HSP90 client kinases, but bare protein binding is uninformative and not elevated to core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: Large neurodegeneration interactome capturing many partners (e.g. MYC, p53), none being core chaperones. Bare protein binding is uninformative.
Reason: High-throughput interactome partners unrelated to HOP's chaperone-organizing function; uninformative protein binding.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex interactome capturing HOP interactions (partners O15484, Q8IWD4). Bare protein binding is uninformative and these are not core chaperone partners.
Reason: Records real high-throughput interactions but uninformative protein binding; not core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:35140242
Human transcription factor protein interaction networks. 		KEEP AS NON CORE
Summary: Interaction with p53 (P04637). Bare protein binding is uninformative; p53 is an HSP90 client but this is a generic binding annotation.
Reason: Real interaction with an HSP90 client (p53), but bare protein binding is uninformative; not core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		MODIFY
Summary: Chaperome interaction-landscape study capturing HOP with HSP90AB1 (P08238). Bare protein binding is uninformative; the meaningful partner is HSP90.
Reason: WITH partner HSP90AB1 (P08238); precisely captured as Hsp90 protein binding.
Proposed replacements: Hsp90 protein binding
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Multimodal cell-maps interactome (partner Q8IWD4). Bare protein binding is uninformative.
Reason: Records a real high-throughput interaction but uninformative protein binding; not core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005634 nucleus
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence-similarity-based nuclear localization, consistent with HOP's documented nuclear pool.
Reason: Consistent with UniProt Nucleus location; nuclear pool is real but non-core relative to the cytoplasmic chaperone-organizing role.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity-based cytoplasm localization, consistent with HOP's principal compartment.
Reason: Matches UniProt subcellular location; cytoplasm is the genuine principal compartment.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0120293 dynein axonemal particle
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence-similarity-based localization to the dynein axonemal particle (ciliated-cell dynein preassembly context).
Reason: Specialized by-similarity localization; peripheral to HOP's general chaperone-organizing function.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Dynein axonemal particle
GO:0051879 Hsp90 protein binding
IPI
PMID:29127155
Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facil... 		ACCEPT
Summary: Experimental evidence for HOP binding HSP90 within the HSP70-HSP90 multichaperone complex. Core molecular function.
Reason: Directly supported; HOP is a defining HSP90-binding component of the multichaperone machine described in this study and in UniProt SUBUNIT.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2
GO:0101031 protein folding chaperone complex
IDA
PMID:29127155
Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facil... 		ACCEPT
Summary: HOP is part of the HSP70-HSP90 multichaperone complex, a folding chaperone complex. This is an accurate and core complex annotation.
Reason: Directly supported by UniProt SUBUNIT (HSP90/HSP70/STIP1/CDC37/PPP5C/p23/TSC1 complex); HOP is a defining organizing subunit.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2
GO:0005515 protein binding
IPI
PMID:23349634
A newly uncovered group of distantly related lysine methyltr... 		KEEP AS NON CORE
Summary: Interaction with the lysine methyltransferase EEF1AKMT3 (Q96AZ1). Bare protein binding is uninformative.
Reason: Records a real interaction but bare protein binding is uninformative; not core.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Interacts with EEF1AKMT3
GO:0032991 protein-containing complex
IDA
PMID:23349634
A newly uncovered group of distantly related lysine methyltr... 		KEEP AS NON CORE
Summary: Generic protein-containing complex annotation from a methyltransferase study. Less informative than the specific HSP70-HSP90 multichaperone complex term.
Reason: Generic complex term; the informative complex annotation is GO:0101031 (HSP70-HSP90 multichaperone complex).
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Interacts with EEF1AKMT3
GO:0005515 protein binding
IPI
PMID:24880080
SMYD2-dependent HSP90 methylation promotes cancer cell proli... 		MODIFY
Summary: Interaction with HSP90AB1 (P08238), modulated by SMYD2-dependent HSP90AB1 methylation. Bare protein binding is uninformative; the meaningful partner is HSP90.
Reason: WITH partner HSP90AB1 (P08238); precisely captured as Hsp90 protein binding.
Proposed replacements: Hsp90 protein binding
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Interacts with HSP90AB1; upon SMYD2-dependent HSP90AB1 methylation
GO:0005515 protein binding
IPI
PMID:23431407
Distinct roles of molecular chaperones HSP90ฮฑ and HSP90ฮฒ in ... 		KEEP AS NON CORE
Summary: Interaction with partner P56696. Bare protein binding is uninformative and not part of HOP's core chaperone function.
Reason: Records a real interaction but bare protein binding is uninformative; not core.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0005515 protein binding
GO:0005515 protein binding
IPI
PMID:27353360
The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... 		MODIFY
Summary: Interaction with HSP90AA1 (P07900) and the FLCN/FNIP co-chaperone module. Bare protein binding is uninformative; the meaningful partner is HSP90.
Reason: WITH partner HSP90AA1 (P07900); precisely captured as Hsp90 protein binding, a core HOP function.
Proposed replacements: Hsp90 protein binding
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
Acts as a co-chaperone for HSP90AA1
GO:0005829 cytosol
TAS
Reactome:R-HSA-3371503 		ACCEPT
Summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
Reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-5618085 		ACCEPT
Summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
Reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-5618098 		ACCEPT
Summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
Reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-5618105 		ACCEPT
Summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
Reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-5618107 		ACCEPT
Summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
Reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-5618110 		ACCEPT
Summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
Reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-9696271 		ACCEPT
Summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
Reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0003723 RNA binding
HDA
PMID:22658674
Insights into RNA biology from an atlas of mammalian mRNA-bi... 		MARK AS OVER ANNOTATED
Summary: mRNA-interactome-capture detection of HOP as an RNA-binder. No characterized RNA-dependent function for HOP exists.
Reason: High-throughput RNA-interactome capture without a validated functional role; not part of HOP's chaperone-organizing function.
Supporting Evidence:
file:human/STIP1/STIP1-goa.tsv
GO:0003723 RNA binding
GO:0005634 nucleus
TAS
PMID:16130169
Proteomics of human umbilical vein endothelial cells applied... 		KEEP AS NON CORE
Summary: Curated nuclear localization of HOP, consistent with its documented nuclear pool.
Reason: Nuclear pool is real (UniProt lists Nucleus) but non-core relative to the cytoplasmic chaperone-organizing role.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005634 nucleus
TAS
PMID:1569099
Molecular cloning and expression of a transformation-sensiti... 		KEEP AS NON CORE
Summary: Early curated nuclear localization of HOP/p60.
Reason: Consistent with the documented nuclear pool; non-core relative to the cytoplasmic function.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005794 Golgi apparatus
TAS
PMID:1569099
Molecular cloning and expression of a transformation-sensiti... 		KEEP AS NON CORE
Summary: Early curated Golgi localization of HOP/p60. Not corroborated by the current UniProt subcellular-location record (cytoplasm/nucleus/dynein axonemal particle).
Reason: Historical localization not supported as a principal compartment in current UniProt; peripheral to HOP's cytoplasmic chaperone function.
Supporting Evidence:
file:human/STIP1/STIP1-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm

Core Functions

Hsp70-Hsp90 organizing protein (HOP); a TPR-domain adaptor co-chaperone that binds HSP90 (via TPR2A/TPR2B) and bridges it to HSP70/HSC70 (via TPR1), coordinating transfer of client proteins from HSP70 to HSP90.

Molecular Function:
Hsp90 protein binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/STIP1/STIP1-uniprot.txt
    Mediates the association of the molecular chaperones HSPA8/HSC70 and HSP90
  • file:human/STIP1/STIP1-uniprot.txt
    The TPR 4, 5 and 6 repeats (also called TPR2A domain) and TPR 7, 8 and 9 repeats (also called TPR2B domain) interact with HSP90.

Component of the HSP70-HSP90 multichaperone machine that organizes client maturation; HOP acts as a scaffold without catalytic activity, holding HSP90 in a client-loading-competent state.

Molecular Function:
Hsp90 protein binding
Cellular Locations:
cytoplasm
In Complex:
protein folding chaperone complex
Supporting Evidence:
  • file:human/STIP1/STIP1-uniprot.txt
    Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs using sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:1569099
Molecular cloning and expression of a transformation-sensitive human protein containing the TPR motif and sharing identity to the stress-inducible yeast protein STI1.
PMID:16130169
Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
PMID:20029029
Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
PMID:21170051
Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.
PMID:21360678
Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5.
PMID:22658674
Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
PMID:23349634
A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.
  • HOP/STIP1 interacts with the methyltransferase EEF1AKMT3.
PMID:23431407
Distinct roles of molecular chaperones HSP90ฮฑ and HSP90ฮฒ in the biogenesis of KCNQ4 channels.
PMID:24880080
SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation.
PMID:25036637
A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  • HOP/STIP1 is a hub co-chaperone within the HSP90 module, interacting with HSP90AA1/HSP90AB1.
PMID:27353360
The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.
  • HOP/STIP1 acts as a co-chaperone for HSP90AA1; its interaction with HSP90 modulates the chaperone cycle.
PMID:28330616
Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:29127155
Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients.
  • HOP/STIP1 is a component of the HSP70-HSP90 multichaperone complex (with CDC37, PPP5C, p23, TSC1) that matures kinase and non-kinase clients.
PMID:31980649
Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35140242
Human transcription factor protein interaction networks.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
Reactome:R-HSA-3371503
HSF1 activation / cytosolic chaperone pathway
Reactome:R-HSA-5618085
Cytosolic chaperone (HSP90) pathway
Reactome:R-HSA-5618098
Cytosolic chaperone (HSP90) pathway
Reactome:R-HSA-5618105
Cytosolic chaperone (HSP90) pathway
Reactome:R-HSA-5618107
Cytosolic chaperone (HSP90) pathway
Reactome:R-HSA-5618110
Cytosolic chaperone (HSP90) pathway
Reactome:R-HSA-9696271
Cytosolic chaperone (HSP90) pathway
file:human/STIP1/STIP1-uniprot.txt
UniProt entry P31948 (STIP1_HUMAN), stress-induced phosphoprotein 1 / HOP
  • HOP/STIP1 is a TPR-domain co-chaperone that mediates the association of HSC70/HSPA8 and HSP90; TPR1 binds HSC70 and TPR2A/TPR2B bind HSP90; it is part of the HSP70-HSP90 multichaperone complex and is cytoplasmic/nuclear.

Suggested Questions for Experts

Q: How is the HOP-mediated HSP70-to-HSP90 client handoff regulated in human cells, and is HOP strictly required or can clients transfer via HOP-independent routes (as suggested in some organisms)?

Q: What determines the cytoplasmic versus nuclear partitioning of HOP, and does the nuclear pool have a chaperone-independent function?

Q: Do the alternative HOP isoforms (P31948-2, P31948-3) differ in TPR-domain composition and thus in HSP70/HSP90 binding or client specificity?

Suggested Experiments

Experiment: Reconstitute the HSP70-HOP-HSP90 client-transfer reaction in vitro with a model client (e.g. a kinase or steroid receptor) and TPR-domain point mutants to dissect the HSP70-binding (TPR1) versus HSP90-binding (TPR2A/2B) contributions to handoff.

Experiment: HOP knockout/knockdown followed by client stability profiling (kinases, steroid receptors) to quantify HOP dependence of the HSP90 clientele in human cells.

Experiment: Crosslinking-MS or cryo-EM of the human HSP70-HOP-HSP90 intermediate to define the architecture of the client-loading complex.

๐Ÿ“š Additional Documentation

Notes

(STIP1-notes.md)

STIP1 (HOP / p60 / Hsp70-Hsp90 organizing protein) โ€” research notes

UniProt: P31948 (STIP1_HUMAN). Alt names: Hop, p60, NY-REN-11.

Core identity

TPR-domain adaptor co-chaperone that simultaneously binds HSP70 (HSPA8/HSC70) and
HSP90, physically bridging the two chaperone systems to mediate client transfer from
HSP70 to HSP90. It has NO catalytic activity; it is a scaffold/adaptor. Avoid "protein
binding" as core; use Hsp70/Hsp90 binding.

  • [file:human/STIP1/STIP1-uniprot.txt "FUNCTION: Acts as a co-chaperone for HSP90AA1 (PubMed:27353360). Mediates the association of the molecular chaperones HSPA8/HSC70 and HSP90"]
  • [file:human/STIP1/STIP1-uniprot.txt "SUBUNIT: Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2"]
  • [file:human/STIP1/STIP1-uniprot.txt "DOMAIN: The TPR 1 repeat interacts with the C-terminal of HSC70. The TPR 4, 5 and 6 repeats (also called TPR2A domain) and TPR 7, 8 and 9 repeats (also called TPR2B domain) interact with HSP90."]
  • [file:human/STIP1/STIP1-uniprot.txt "SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Dynein axonemal particle"]

Mechanism

Classic HOP model: TPR1 binds HSC70 C-terminal EEVD; TPR2A binds HSP90 C-terminal MEEVD.
HOP holds HSP90 in an open conformation and recruits HSP70-bound client for handoff. It
is displaced later in the cycle by p23/PTGES3 and other co-chaperones.

GO annotation review (goa.tsv)

Partner ID map: P08238=HSP90AB1; P07900=HSP90AA1; P04626=ERBB2; P00533=EGFR;
P53041=PPP5C (TPR co-chaperone); Q8IWD4=? small interactome; others mostly HT/unrelated.

  • GO:0051879 Hsp90 protein binding (IBA, IPI PMID:29127155): CORE MF. ACCEPT.
  • GO:0101031 protein folding chaperone complex part_of (IDA PMID:29127155): the HSP70-HSP90
    multichaperone machine; HOP is a defining component. ACCEPT.
  • GO:0005737 cytoplasm (IEA, ISS): CORE localization. ACCEPT.
  • GO:0005634 nucleus (IEA, ISS, TAS PMID:16130169, PMID:1569099): HOP shuttles to nucleus;
    documented. KEEP_AS_NON_CORE / ACCEPT (UniProt lists Nucleus).
  • GO:0120293 dynein axonemal particle (IEA, ISS): by similarity to other species (cilia
    context); HOP/co-chaperones implicated in axonemal dynein assembly. KEEP_AS_NON_CORE.
  • GO:0005829 cytosol (TAS Reactome x7): CORE cytosolic localization. ACCEPT (one representative)
    / KEEP_AS_NON_CORE for redundant pathway-context ones.
  • GO:0005794 Golgi apparatus (TAS PMID:1569099): older localization; minor. KEEP_AS_NON_CORE.
  • GO:0003723 RNA binding (HDA PMID:22658674): mRNA-interactome capture; no characterized RNA
    function. MARK_AS_OVER_ANNOTATED.
  • GO:0032991 protein-containing complex part_of (IDA PMID:23349634): generic; HOP in a
    methyltransferase-substrate complex context. KEEP_AS_NON_CORE.
  • GO:0005515 protein binding (many IPI): HSP90 partners (P08238/P07900) -> MODIFY to Hsp90
    protein binding; PPP5C/clients (EGFR, ERBB2) -> KEEP_AS_NON_CORE (real but generic);
    unrelated HT (p53, MYC, etc., PMID:32814053; PMID:35140242) -> MARK_AS_OVER_ANNOTATED.

Core function synthesis

  1. Hsp70-Hsp90 organizing protein: TPR adaptor binding both HSC70 and HSP90 (GO:0051879
    Hsp90 protein binding + Hsp70 binding GO:0030544), bridging client transfer.
  2. Component of the HSP70-HSP90 multichaperone complex (GO:0101031).
  3. Cytoplasmic (also nuclear); no catalytic activity.

Pn Notes

(STIP1-pn-notes.md)

STIP1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: P31948
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: STIP1 (stress-induced phosphoprotein 1), better known as HOP (Hsp70-Hsp90 organizing protein) or p60, is a cytoplasmic (and partly nuclear) TPR-domain adaptor co-chaperone. It contains three TPR (tetratricopeptide repeat) domains. The TPR1 domain binds the C-terminal EEVD motif of HSP70 (HSPA8/HSC70), while the TPR2A and TPR2B domains bind the C-terminal MEEVD motif of HSP90. By simultaneously engaging both chaperones, HOP physically bridges the HSP70 and HSP90 systems and coordinates the transfer of client proteins from HSP70 to HSP90 during the chaperone cycle. HOP has no catalytic activity; it functions as a scaffold/adaptor that modulates HSP90 conformation and client maturation. It is a defining component of the HSP70-HSP90 multichaperone machine and participates in the maturation of diverse clients including protein kinases and steroid hormone receptors.
  • Existing/core annotation action counts: ACCEPT: 12; KEEP_AS_NON_CORE: 19; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 6

PN Consistency Summary

  • Consistency: Partial. Review and notes correctly frame HOP as a non-catalytic TPR scaffold bridging HSP70โ†”HSP90 (core MF GO:0051879 Hsp90 binding; in_complex GO:0101031). But the review contains NO autophagy/CMA/microautophagy/lysosome content at all (confirmed in both YAML and notes), whereas PN asserts three ALP roles. This is a real coverage gap, not a contradiction.
  • PN story / NEW pressure: PN projects CMA substrate-selection (GO:0061684, GO:0061740) and late endosomal microautophagy (GO:0061738) โ€” all verified real, all new_to_goa (GOA confirms no autophagy rows). HOP/HSPA8 participation in eMI and CMA substrate handoff is literature-supported (Nat Rev MCB CMA review). ADD is defensible for these as non-core BPs if full text supports HOP specifically.
  • Evidence alignment: PN cites the Nat Rev MCB CMA review; review references are UniProt/HSP90-cycle papers (e.g. PMID:27353360). No overlap on the autophagy literature.
  • Verdict: Consistent on the chaperone core but review under-covers the ALP/CMA story PN documents. Recommended edits: consider adding GO:0061684 / GO:0061740 / GO:0061738 as KEEP_AS_NON_CORE pending full-text verification of HOP-specific evidence [YAML]; cite the CMA review [REF]. Do not add GO:0031072 (broader, already entailed) [MAP].

Full Consistency Review

  • UniProt: P31948 (HOP) ยท batch: proteostasis-batch-2026-06-07b ยท review status: COMPLETE
  • PN placement: Cytonuclear|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone|CC-TPR and STI/HOP domain; ALP|Microautophagy|Endosomal microautophagy; ALP|CMA|Effectors|Substrate selection ; PN-node mapping: mapped โ†’ GO:0031072 (HSP binding, entailed_by_goa_closure), GO:0061738 (late endosomal microautophagy, new), GO:0061684 (CMA, new), GO:0061740 (CMA targeting, new)
  • Consistency: Partial. Review and notes correctly frame HOP as a non-catalytic TPR scaffold bridging HSP70โ†”HSP90 (core MF GO:0051879 Hsp90 binding; in_complex GO:0101031). But the review contains NO autophagy/CMA/microautophagy/lysosome content at all (confirmed in both YAML and notes), whereas PN asserts three ALP roles. This is a real coverage gap, not a contradiction.
  • PN story / NEW pressure: PN projects CMA substrate-selection (GO:0061684, GO:0061740) and late endosomal microautophagy (GO:0061738) โ€” all verified real, all new_to_goa (GOA confirms no autophagy rows). HOP/HSPA8 participation in eMI and CMA substrate handoff is literature-supported (Nat Rev MCB CMA review). ADD is defensible for these as non-core BPs if full text supports HOP specifically.
  • Mapping strategy: GO:0031072 projection is BROADER than the review's GO:0051879 (Hsp90 binding is_a heat shock protein binding, OLS-verified) but PN self-flags it entailed_by_goa_closure โ†’ redundant, no action. The novel value is the three ALP terms.
  • Evidence alignment: PN cites the Nat Rev MCB CMA review; review references are UniProt/HSP90-cycle papers (e.g. PMID:27353360). No overlap on the autophagy literature.
  • Verdict: Consistent on the chaperone core but review under-covers the ALP/CMA story PN documents. Recommended edits: consider adding GO:0061684 / GO:0061740 / GO:0061738 as KEEP_AS_NON_CORE pending full-text verification of HOP-specific evidence [YAML]; cite the CMA review [REF]. Do not add GO:0031072 (broader, already entailed) [MAP].

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/STIP1/STIP1-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Cytonuclear proteostasis | Chaperone | HSP70-HSP90 system integration | HSP70-HSP90 joint cochaperone | CC-TPR and STI/HOP domain containing

  • UniProt: P31948
  • In branches: CY, ALP
  • PN-node mapping records (path + ancestors):
    • [subtype] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone|CC-TPR and STI/HOP domain containing
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a family/domain/subtype label. It classifies PN members but is not itself a GO annotation target; any functional assertion should come from a parent role mapping or gene-specific review.
    • [type] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0031072 heat shock protein binding]
      rationale: This PN type groups joint HSP70/HSP90 cochaperones. The shared mechanistic assertion is binding heat-shock-protein chaperones, while narrower domain labels remain non-mapping unless they carry an independent activity.
    • [group] Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Autophagy-Lysosome Pathway | Microautophagy | Endosomal microautophagy

  • UniProt: P31948
  • In branches: CY, ALP
  • PN-node mapping records (path + ancestors):
    • [group] Autophagy-Lysosome Pathway|Microautophagy|Endosomal microautophagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061738 late endosomal microautophagy]
      rationale: This PN group contains HSPA8/co-chaperone machinery for endosomal microautophagy. The matching GO process is late endosomal microautophagy.
    • [class] Autophagy-Lysosome Pathway|Microautophagy
      status=context_only scope=too_broad_to_propagate GO=[GO:0016237 microautophagy]
      rationale: The class names a real GO process, but the subtree includes machinery components and mitochondrion-derived-vesicle contexts as well as process labels. Propagation is restricted to narrower nodes.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Autophagy-Lysosome Pathway | Chaperone-mediated autophagy | Effectors of chaperone-mediated autophagy | Substrate selection

  • UniProt: P31948
  • In branches: CY, ALP
  • Notes: An HSP90 cochaperone. Works with HSPA8 in autophagy substrate selection. Also a component of the complex at the lysosomal membrane that facilitates the unfolding of substrates.
  • PN references (titles):
    • The coming of age of chaperone-mediated autophagy | Nature Reviews Molecular Cell Biology
  • PN-node mapping records (path + ancestors):
    • [type] Autophagy-Lysosome Pathway|Chaperone-mediated autophagy|Effectors of chaperone-mediated autophagy|Substrate selection
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061740 protein targeting to lysosome involved in chaperone-mediated autophagy]
      rationale: This leaf denotes substrate-selection machinery for CMA. The GO protein-targeting term preserves the mechanistic role without relying on broad class-level CMA propagation.
    • [group] Autophagy-Lysosome Pathway|Chaperone-mediated autophagy|Effectors of chaperone-mediated autophagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061684 chaperone-mediated autophagy]
      rationale: This group covers direct CMA machinery and substrate-selection effectors, unlike the broader CMA class that also includes regulators. Propagation to chaperone-mediated autophagy is appropriate at this narrower level.
    • [class] Autophagy-Lysosome Pathway|Chaperone-mediated autophagy
      status=context_only scope=too_broad_to_propagate GO=[GO:0061684 chaperone-mediated autophagy]
      rationale: The class label matches the GO CMA process, but the subtree includes both effectors and positive or negative modulators. The relation is retained as context so modulators are not projected as direct CMA participants unless a narrower node supports it.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (4)

  • GO:0031072 heat shock protein binding | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Cytonuclear proteostasis|Chaperone|HSP70-HSP90 system integration|HSP70-HSP90 joint cochaperone
  • GO:0061738 late endosomal microautophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Microautophagy|Endosomal microautophagy
  • GO:0061684 chaperone-mediated autophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Chaperone-mediated autophagy|Effectors of chaperone-mediated autophagy
  • GO:0061740 protein targeting to lysosome involved in chaperone-mediated autophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Chaperone-mediated autophagy|Effectors of chaperone-mediated autophagy|Substrate selection

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

๐Ÿ“„ View Raw YAML

 
id: P31948
gene_symbol: STIP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: STIP1 (stress-induced phosphoprotein 1), better known as HOP (Hsp70-Hsp90 organizing protein) or p60, is a cytoplasmic (and partly nuclear) TPR-domain adaptor co-chaperone. It contains three TPR (tetratricopeptide repeat) domains. The TPR1 domain binds the C-terminal EEVD motif of HSP70 (HSPA8/HSC70), while the TPR2A and TPR2B domains bind the C-terminal MEEVD motif of HSP90. By simultaneously engaging both chaperones, HOP physically bridges the HSP70 and HSP90 systems and coordinates the transfer of client proteins from HSP70 to HSP90 during the chaperone cycle. HOP has no catalytic activity; it functions as a scaffold/adaptor that modulates HSP90 conformation and client maturation. It is a defining component of the HSP70-HSP90 multichaperone machine and participates in the maturation of diverse clients including protein kinases and steroid hormone receptors.
alternative_products:
- name: '1'
  id: P31948-1
- name: '2'
  id: P31948-2
  sequence_note: VSP_055034
- name: '3'
  id: P31948-3
  sequence_note: VSP_055035
existing_annotations:
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: HOP binds HSP90 directly via its TPR2A/TPR2B domains (HSP90 C-terminal MEEVD). This is a core molecular function.
    action: ACCEPT
    reason: Directly supported by UniProt FUNCTION/DOMAIN and by experimental HSP90 interaction data; HSP90 binding is central to HOP's adaptor role.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: The TPR 4, 5 and 6 repeats (also called TPR2A domain) and TPR 7, 8 and 9 repeats (also called TPR2B domain) interact with HSP90.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: HOP is detected in the nucleus in addition to the cytoplasm; nuclear shuttling is documented.
    action: KEEP_AS_NON_CORE
    reason: UniProt lists Nucleus as a subcellular location; nuclear pool is real but HOP's principal chaperone-organizing function is cytoplasmic.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: HOP is predominantly cytoplasmic, where it organizes the HSP70-HSP90 machine.
    action: ACCEPT
    reason: Matches UniProt subcellular location; cytoplasm is the genuine principal compartment of HOP.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0120293
    label: dynein axonemal particle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: By-similarity localization to the dynein axonemal particle, reflecting a role of HOP/co-chaperones in cytoplasmic preassembly of axonemal dynein in ciliated cells.
    action: KEEP_AS_NON_CORE
    reason: Specialized, by-similarity localization in ciliated-cell contexts; peripheral to HOP's general cytoplasmic chaperone-organizing function.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Dynein axonemal particle
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20029029
  qualifier: enables
  review:
    summary: Interaction with EGFR (P00533), an HSP90 client kinase. Bare protein binding is uninformative; the interaction is consistent with HOP's role in client maturation but is a generic binding term.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with an HSP90 client (EGFR), but bare protein binding is uninformative and not elevated to core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  qualifier: enables
  review:
    summary: High-throughput interaction (partner Q96AP0). Bare protein binding is uninformative and the partner is not part of HOP's core chaperone function.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative; not core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21170051
  qualifier: enables
  review:
    summary: Interaction with HSP90AB1 (P08238). Bare protein binding is uninformative; this HSP90 interaction is better captured as Hsp90 protein binding.
    action: MODIFY
    reason: The WITH partner is HSP90AB1 (P08238); the interaction is precisely captured as Hsp90 protein binding, a core HOP function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21360678
  qualifier: enables
  review:
    summary: Interaction with PPP5C (P53041), a TPR-domain HSP90 co-chaperone phosphatase. Bare protein binding is uninformative; the partner is chaperone-machinery-related.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with a co-chaperone (PPP5C) within the HSP90 machine, but bare protein binding is uninformative; not elevated to core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Quantitative chaperone interaction network capturing HOP with HSP90AB1 (P08238) and CDC37L1 (Q7L3B6) among others. Bare protein binding is uninformative; the meaningful partner is HSP90.
    action: MODIFY
    reason: WITH partners include HSP90AB1 (P08238); the chaperone-network interaction is precisely captured as Hsp90 protein binding.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28330616
  qualifier: enables
  review:
    summary: Interaction with PPP5C (P53041), an HSP90 co-chaperone. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with a chaperone-machinery component but uninformative protein binding term; not core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Binary interactome capturing HOP with HSP90AB1 (P08238) and another partner. Bare protein binding is uninformative; the meaningful partner is HSP90.
    action: MODIFY
    reason: WITH partner HSP90AB1 (P08238); precisely captured as Hsp90 protein binding.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: Interaction with EGFR (P00533) and ERBB2 (P04626), HSP90 client kinases. Bare protein binding is uninformative; consistent with HOP's client-maturation role.
    action: KEEP_AS_NON_CORE
    reason: Records real interactions with HSP90 client kinases, but bare protein binding is uninformative and not elevated to core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Large neurodegeneration interactome capturing many partners (e.g. MYC, p53), none being core chaperones. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome partners unrelated to HOP's chaperone-organizing function; uninformative protein binding.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex interactome capturing HOP interactions (partners O15484, Q8IWD4). Bare protein binding is uninformative and these are not core chaperone partners.
    action: KEEP_AS_NON_CORE
    reason: Records real high-throughput interactions but uninformative protein binding; not core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35140242
  qualifier: enables
  review:
    summary: Interaction with p53 (P04637). Bare protein binding is uninformative; p53 is an HSP90 client but this is a generic binding annotation.
    action: KEEP_AS_NON_CORE
    reason: Real interaction with an HSP90 client (p53), but bare protein binding is uninformative; not core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Chaperome interaction-landscape study capturing HOP with HSP90AB1 (P08238). Bare protein binding is uninformative; the meaningful partner is HSP90.
    action: MODIFY
    reason: WITH partner HSP90AB1 (P08238); precisely captured as Hsp90 protein binding.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome (partner Q8IWD4). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real high-throughput interaction but uninformative protein binding; not core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based nuclear localization, consistent with HOP's documented nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Consistent with UniProt Nucleus location; nuclear pool is real but non-core relative to the cytoplasmic chaperone-organizing role.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based cytoplasm localization, consistent with HOP's principal compartment.
    action: ACCEPT
    reason: Matches UniProt subcellular location; cytoplasm is the genuine principal compartment.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0120293
    label: dynein axonemal particle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based localization to the dynein axonemal particle (ciliated-cell dynein preassembly context).
    action: KEEP_AS_NON_CORE
    reason: Specialized by-similarity localization; peripheral to HOP's general chaperone-organizing function.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Dynein axonemal particle
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IPI
  original_reference_id: PMID:29127155
  qualifier: enables
  review:
    summary: Experimental evidence for HOP binding HSP90 within the HSP70-HSP90 multichaperone complex. Core molecular function.
    action: ACCEPT
    reason: Directly supported; HOP is a defining HSP90-binding component of the multichaperone machine described in this study and in UniProt SUBUNIT.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IDA
  original_reference_id: PMID:29127155
  qualifier: part_of
  review:
    summary: HOP is part of the HSP70-HSP90 multichaperone complex, a folding chaperone complex. This is an accurate and core complex annotation.
    action: ACCEPT
    reason: Directly supported by UniProt SUBUNIT (HSP90/HSP70/STIP1/CDC37/PPP5C/p23/TSC1 complex); HOP is a defining organizing subunit.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23349634
  qualifier: enables
  review:
    summary: Interaction with the lysine methyltransferase EEF1AKMT3 (Q96AZ1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative; not core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Interacts with EEF1AKMT3
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:23349634
  qualifier: part_of
  review:
    summary: Generic protein-containing complex annotation from a methyltransferase study. Less informative than the specific HSP70-HSP90 multichaperone complex term.
    action: KEEP_AS_NON_CORE
    reason: Generic complex term; the informative complex annotation is GO:0101031 (HSP70-HSP90 multichaperone complex).
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Interacts with EEF1AKMT3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24880080
  qualifier: enables
  review:
    summary: Interaction with HSP90AB1 (P08238), modulated by SMYD2-dependent HSP90AB1 methylation. Bare protein binding is uninformative; the meaningful partner is HSP90.
    action: MODIFY
    reason: WITH partner HSP90AB1 (P08238); precisely captured as Hsp90 protein binding.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Interacts with HSP90AB1; upon SMYD2-dependent HSP90AB1 methylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23431407
  qualifier: enables
  review:
    summary: Interaction with partner P56696. Bare protein binding is uninformative and not part of HOP's core chaperone function.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative; not core.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0005515 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27353360
  qualifier: enables
  review:
    summary: Interaction with HSP90AA1 (P07900) and the FLCN/FNIP co-chaperone module. Bare protein binding is uninformative; the meaningful partner is HSP90.
    action: MODIFY
    reason: WITH partner HSP90AA1 (P07900); precisely captured as Hsp90 protein binding, a core HOP function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: Acts as a co-chaperone for HSP90AA1
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3371503
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618085
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618098
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618105
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618107
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5618110
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9696271
  qualifier: located_in
  review:
    summary: Curated (Reactome) cytosolic localization, consistent with HOP's cytoplasmic chaperone role.
    action: ACCEPT
    reason: Cytosol is the genuine principal compartment of HOP; consistent with UniProt (one of several redundant Reactome cytosol annotations).
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: mRNA-interactome-capture detection of HOP as an RNA-binder. No characterized RNA-dependent function for HOP exists.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput RNA-interactome capture without a validated functional role; not part of HOP's chaperone-organizing function.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-goa.tsv
      supporting_text: GO:0003723 RNA binding
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:16130169
  qualifier: located_in
  review:
    summary: Curated nuclear localization of HOP, consistent with its documented nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Nuclear pool is real (UniProt lists Nucleus) but non-core relative to the cytoplasmic chaperone-organizing role.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:1569099
  qualifier: located_in
  review:
    summary: Early curated nuclear localization of HOP/p60.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the documented nuclear pool; non-core relative to the cytoplasmic function.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: TAS
  original_reference_id: PMID:1569099
  qualifier: located_in
  review:
    summary: Early curated Golgi localization of HOP/p60. Not corroborated by the current UniProt subcellular-location record (cytoplasm/nucleus/dynein axonemal particle).
    action: KEEP_AS_NON_CORE
    reason: Historical localization not supported as a principal compartment in current UniProt; peripheral to HOP's cytoplasmic chaperone function.
    supported_by:
    - reference_id: file:human/STIP1/STIP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs using sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1569099
  title: 'Molecular cloning and expression of a transformation-sensitive human protein containing the TPR motif and sharing identity to the stress-inducible yeast protein STI1.'
  findings: []
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
  findings: []
- id: PMID:20029029
  title: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
  findings: []
- id: PMID:21170051
  title: Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.
  findings: []
- id: PMID:21360678
  title: Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:23349634
  title: A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.
  findings:
  - statement: HOP/STIP1 interacts with the methyltransferase EEF1AKMT3.
    reference_section_type: RESULTS
- id: PMID:23431407
  title: Distinct roles of molecular chaperones HSP90ฮฑ and HSP90ฮฒ in the biogenesis of KCNQ4 channels.
  findings: []
- id: PMID:24880080
  title: SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  findings:
  - statement: HOP/STIP1 is a hub co-chaperone within the HSP90 module, interacting with HSP90AA1/HSP90AB1.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; the quantitative chaperone-interaction network places HOP/STIP1 as a hub co-chaperone of the HSP90 module interacting with HSP90AA1/HSP90AB1, supporting its core Hsp70-Hsp90 organizing/adaptor function (GO:0051879).
- id: PMID:27353360
  title: The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.
  findings:
  - statement: HOP/STIP1 acts as a co-chaperone for HSP90AA1; its interaction with HSP90 modulates the chaperone cycle.
    reference_section_type: RESULTS
- id: PMID:28330616
  title: Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:29127155
  title: Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients.
  findings:
  - statement: HOP/STIP1 is a component of the HSP70-HSP90 multichaperone complex (with CDC37, PPP5C, p23, TSC1) that matures kinase and non-kinase clients.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: GOA-anchored (this PMID supports GO:0051879 Hsp90 protein binding, IPI, and GO:0101031 chaperone complex in STIP1-goa.tsv); corroborates STIP1/HOP as a component of the HSP70-HSP90 multichaperone machine maturing kinase/non-kinase clients.
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35140242
  title: Human transcription factor protein interaction networks.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-3371503
  title: HSF1 activation / cytosolic chaperone pathway
  findings: []
- id: Reactome:R-HSA-5618085
  title: Cytosolic chaperone (HSP90) pathway
  findings: []
- id: Reactome:R-HSA-5618098
  title: Cytosolic chaperone (HSP90) pathway
  findings: []
- id: Reactome:R-HSA-5618105
  title: Cytosolic chaperone (HSP90) pathway
  findings: []
- id: Reactome:R-HSA-5618107
  title: Cytosolic chaperone (HSP90) pathway
  findings: []
- id: Reactome:R-HSA-5618110
  title: Cytosolic chaperone (HSP90) pathway
  findings: []
- id: Reactome:R-HSA-9696271
  title: Cytosolic chaperone (HSP90) pathway
  findings: []
- id: file:human/STIP1/STIP1-uniprot.txt
  title: UniProt entry P31948 (STIP1_HUMAN), stress-induced phosphoprotein 1 / HOP
  findings:
  - statement: HOP/STIP1 is a TPR-domain co-chaperone that mediates the association of HSC70/HSPA8 and HSP90; TPR1 binds HSC70 and TPR2A/TPR2B bind HSP90; it is part of the HSP70-HSP90 multichaperone complex and is cytoplasmic/nuclear.
    reference_section_type: OTHER
core_functions:
- description: Hsp70-Hsp90 organizing protein (HOP); a TPR-domain adaptor co-chaperone that binds HSP90 (via TPR2A/TPR2B) and bridges it to HSP70/HSC70 (via TPR1), coordinating transfer of client proteins from HSP70 to HSP90.
  molecular_function:
    id: GO:0051879
    label: Hsp90 protein binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/STIP1/STIP1-uniprot.txt
    supporting_text: Mediates the association of the molecular chaperones HSPA8/HSC70 and HSP90
  - reference_id: file:human/STIP1/STIP1-uniprot.txt
    supporting_text: The TPR 4, 5 and 6 repeats (also called TPR2A domain) and TPR 7, 8 and 9 repeats (also called TPR2B domain) interact with HSP90.
- description: Component of the HSP70-HSP90 multichaperone machine that organizes client maturation; HOP acts as a scaffold without catalytic activity, holding HSP90 in a client-loading-competent state.
  molecular_function:
    id: GO:0051879
    label: Hsp90 protein binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/STIP1/STIP1-uniprot.txt
    supporting_text: Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2
  in_complex:
    id: GO:0101031
    label: protein folding chaperone complex
proposed_new_terms: []
suggested_questions:
- question: How is the HOP-mediated HSP70-to-HSP90 client handoff regulated in human cells, and is HOP strictly required or can clients transfer via HOP-independent routes (as suggested in some organisms)?
- question: What determines the cytoplasmic versus nuclear partitioning of HOP, and does the nuclear pool have a chaperone-independent function?
- question: Do the alternative HOP isoforms (P31948-2, P31948-3) differ in TPR-domain composition and thus in HSP70/HSP90 binding or client specificity?
suggested_experiments:
- description: Reconstitute the HSP70-HOP-HSP90 client-transfer reaction in vitro with a model client (e.g. a kinase or steroid receptor) and TPR-domain point mutants to dissect the HSP70-binding (TPR1) versus HSP90-binding (TPR2A/2B) contributions to handoff.
- description: HOP knockout/knockdown followed by client stability profiling (kinases, steroid receptors) to quantify HOP dependence of the HSP90 clientele in human cells.
- description: Crosslinking-MS or cryo-EM of the human HSP70-HOP-HSP90 intermediate to define the architecture of the client-loading complex.