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.
| 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 HSP90Ξ± and HSP90Ξ² 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 |
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Download this section (compressed HTML)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?
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.
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