St13

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: Hip/St13 participates in protein folding as a co-chaperone of the Hsc70 system. Hohfeld et al. (PMID:7585962) showed that Hip cooperates with Hsc70/Hsp40 in the folding reaction cycle. The IBA annotation from phylogenetic inference is consistent with the known biology. Reason: Protein folding is a core biological process for Hip. As a co-chaperone that stabilizes the substrate-binding state of Hsc70, Hip directly participates in the protein folding cycle. The IBA annotation is phylogenetically sound and supported by multiple experimental studies. Supporting Evidence: PMID:7585962 The Hsc70-interacting protein Hip, a tetratricopeptide repeat protein, participates in the regulation of the eukaryotic 70 kDa heat shock cognate Hsc70. file:rat/St13/St13-deep-research-falcon.md ST13/Hip is a cytosolic Hsp70/Hsc70 co-chaperone that promotes productive protein folding by stabilizing chaperone-client complexes; it is not an enzyme or transporter and does not catalyze a chemical reaction.
GO:0030544 Hsp70 protein binding	IBA GO_REF:0000033	ACCEPT	Summary: Hsp70 protein binding is the core molecular function of Hip. Multiple studies demonstrate direct binding of Hip to the ATPase domain of Hsc70 (PMID:7585962, PMID:8999928, PMID:9528774, PMID:23812373). The IBA annotation is well-supported. Reason: This is the defining molecular function of Hip - direct binding to Hsp70 family members. The IBA annotation is phylogenetically sound and supported by extensive experimental evidence from multiple groups. Supporting Evidence: PMID:7585962 One Hip oligomer binds the ATPase domains of at least two Hsc70 molecules dependent on activation of the Hsc70 ATPase by Hsp40. file:rat/St13/St13-deep-research-falcon.md Hip preferentially binds ADP-bound Hsp70 (reported KD ≈ 8 µM) and binds more weakly to apo Hsp70 (KD ≈ 51 µM), with no detectable binding to ATP-bound Hsp70 under the conditions described; this explains why Hip acts as an ADP-state stabilizer.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location mapping. UniProt annotates St13 to the cytoplasm. Consistent with IDA evidence for cytosol localization (PMID:7585962). Reason: Cytoplasmic localization is well-established and consistent with the more specific cytosol annotation. The IEA annotation is correct though broader than the IDA-supported GO:0005829 (cytosol).
GO:0046983 protein dimerization activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: IEA annotation from InterPro mapping. Hip forms homo-oligomers (tetramers, not dimers). Li et al. (PMID:23812373) solved the crystal structure of the dimerization domain. The N-terminal domain mediates homo-oligomerization (PMID:8999928). While the protein does dimerize as part of tetramer formation, this is a structural property rather than a functional molecular activity. Reason: While Hip does self-associate (forming tetramers via its N-terminal dimerization domain), protein dimerization activity is a structural feature rather than the functional molecular activity of interest. The core function is Hsp70 protein binding (GO:0030544), and the self-association is a prerequisite for this function rather than the function itself.
GO:0005515 protein binding	IPI PMID:21808025 C terminus of Hsc70-interacting protein (CHIP)-mediated degr...	MARK AS OVER ANNOTATED	Summary: IPI annotation from Zhang et al. (2011), a study on CHIP-mediated degradation of hippocampal estrogen receptor-alpha. St13/Hip was identified as an interactor in the context of the Hsc70/CHIP complex. However, GO:0005515 (protein binding) is uninformative for a co-chaperone that has multiple specific binding partners. Reason: Protein binding is too vague for a co-chaperone. Hip has well-characterized specific binding interactions with Hsc70 (GO:0030544), which is already annotated. The generic protein binding term does not add useful functional information.
GO:0042802 identical protein binding	IPI PMID:23812373 Structure and function of Hip, an attenuator of the Hsp70 ch...	ACCEPT	Summary: IPI annotation from Li et al. (2013), who solved crystal structures of the Hip dimerization domain showing direct homotypic interactions. Hip forms homo-oligomers (tetramers) via its N-terminal domain. Reason: The crystal structure (PMID:23812373) provides definitive evidence for identical protein binding. Hip forms functional homo-oligomers, and self-association is required for its co-chaperone function. Supporting Evidence: PMID:23812373 Here we present crystal structures of the dimerization domain and the tetratricopeptide repeat (TPR) domain of rat Hip. file:rat/St13/St13-deep-research-falcon.md An N-terminal dimerization region involved in homo-oligomerization
GO:0005829 cytosol	IDA PMID:7585962 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hs...	ACCEPT	Summary: IDA annotation from Hohfeld et al. (1995), who identified Hip as a cytosolic protein interacting with Hsc70. Hip was purified from reticulocyte lysate, confirming cytosolic localization. Reason: Cytosol localization is well-established from the original identification of Hip as a cytosolic co-chaperone. This is a core cellular component annotation. Supporting Evidence: PMID:7585962 The Hsc70-interacting protein Hip, a tetratricopeptide repeat protein, participates in the regulation of the eukaryotic 70 kDa heat shock cognate Hsc70. file:rat/St13/St13-deep-research-falcon.md Hip/ST13 is described as a cytosolic co-chaperone in reviews and mechanistic summaries, consistent with its role in the cytosolic Hsp70 cycle
GO:0009617 response to bacterium	ISO GO_REF:0000121	UNDECIDED	Summary: ISO annotation transferred from mammalian orthologs via RGD. The connection between Hip/St13 and response to bacterium is not obvious from the known co-chaperone biology. This may relate to the role of Hsp70 chaperones in immune responses, but it is not a core function of Hip itself. Reason: Unable to assess the basis for this annotation without access to the original experimental evidence in the source species. The connection between a cytosolic Hsc70 co-chaperone and response to bacterium is not immediately clear from known Hip biology and may represent an indirect or peripheral effect. Propagation Review Root cause: UNRESOLVED Sources checked: MGI:MGI:1917606 · mouse St13 UNRESOLVED The donor is the mouse St13 ortholog, but the underlying mouse experimental evidence was not accessible here, so whether a Hsc70 co-chaperone acts in a bacterial response or is only indirectly affected could not be determined.
GO:0019904 protein domain specific binding	IDA PMID:8999928 Characterization of functional domains of the eukaryotic co-...	ACCEPT	Summary: IDA annotation from Irmer and Hohfeld (1997), who mapped the Hsc70-binding site of Hip to its TPR domain and showed it interacts specifically with the ATPase domain of Hsc70. This demonstrates domain-specific binding. Reason: The study directly demonstrates that Hip binds specifically to the ATPase domain of Hsc70 through its TPR domain. This is a clear case of protein domain specific binding supported by deletion mapping and in vitro interaction assays. Supporting Evidence: PMID:8999928 the Hsc70-binding site of Hip was mapped to a domain comprising multiple tetratricopeptide repeats and flanking charged alpha-helices. Affinity chromatography confirmed direct interaction of isolated Hip fragments and protein fusions bearing this region with the ATPase domain of Hsc70 in an ATP- and salt-dependent manner. file:rat/St13/St13-deep-research-falcon.md A central TPR domain that mediates Hsp70 NBD binding
GO:0019904 protein domain specific binding	IPI PMID:9528774 The carboxy-terminal domain of Hsc70 provides binding sites ...	ACCEPT	Summary: IPI annotation from Demand et al. (1998), who showed that Hip interacts exclusively with the amino-terminal ATPase domain of Hsc70, while Hsp40 and Hop bind the carboxy-terminal domain. Reason: This study provides complementary evidence for domain-specific binding, demonstrating that Hip binds exclusively to the ATPase domain of Hsc70, separate from the binding sites for Hsp40 and Hop. Supporting Evidence: PMID:9528774 Hip interacts exclusively with the amino-terminal ATPase domain of Hsc70... Hsc70 possesses separate nonoverlapping binding sites for Hsp40, Hip, and Hop.
GO:0030544 Hsp70 protein binding	IPI PMID:9528774 The carboxy-terminal domain of Hsc70 provides binding sites ...	ACCEPT	Summary: IPI annotation from Demand et al. (1998), demonstrating physical interaction between Hip and Hsc70. Consistent with the IBA and IDA annotations for the same term. Reason: Direct physical interaction evidence for Hip binding to Hsc70, consistent with multiple other lines of evidence. Supporting Evidence: PMID:9528774 Hip interacts exclusively with the amino-terminal ATPase domain of Hsc70.
GO:0032564 dATP binding	IDA PMID:9183013 Characterization of the molecular-chaperone function of the ...	ACCEPT	Summary: IDA annotation from Bruce and Churchich (1997), who showed that recombinant Hip recognizes anthraniloyl-dATP, anthraniloyl-ADP, and TNP-ATP by fluorescence measurements, despite not catalyzing ATP hydrolysis. Reason: The experimental evidence directly demonstrates nucleotide recognition by Hip using fluorescence measurements. While Hip does not hydrolyze ATP, it does bind nucleotide analogs. The annotation is supported by the direct assay evidence. Supporting Evidence: PMID:9183013 fluorescence measurements indicated that the chaperone recognizes anthraniloyl-dATP, anthraniloyl-ADP, and 2'-O-trinitrophenyl-ATP.
GO:0032991 protein-containing complex	IDA PMID:9528774 The carboxy-terminal domain of Hsc70 provides binding sites ...	MARK AS OVER ANNOTATED	Summary: IDA annotation from Demand et al. (1998). Hip is part of a multi-protein complex with Hsc70, Hsp40, and other co-chaperones. However, GO:0032991 (protein-containing complex) is extremely generic and uninformative. Reason: While Hip does participate in protein complexes, GO:0032991 is the root term for all protein complexes and provides no useful information about which complex. A more specific complex term would be informative, though no specific GO term exists for the Hsc70/Hip/Hsp40 complex.
GO:0042802 identical protein binding	IPI PMID:8999928 Characterization of functional domains of the eukaryotic co-...	ACCEPT	Summary: IPI annotation from Irmer and Hohfeld (1997), who identified the N-terminal homo-oligomerization domain of Hip. Reason: The study directly demonstrates self-association of Hip through its N-terminal domain, supporting identical protein binding. Supporting Evidence: PMID:8999928 a domain required for homo-oligomerization was identified at the extreme amino terminus of Hip.
GO:0051082 unfolded protein binding	IDA PMID:9183013 Characterization of the molecular-chaperone function of the ...	MODIFY	Summary: IDA annotation from Bruce and Churchich (1997). The paper showed that Hip binds specifically to reduced, carboxymethylated alpha-lactalbumin (a non-native protein) but not the native form. However, Hip was unable to facilitate refolding and actually inhibited it. GO:0051082 is now formally obsolete. Hip functions as a co-chaperone rather than as an independent chaperone that productively handles unfolded substrates. Reason: GO:0051082 (unfolded protein binding) is now formally obsolete. While Bruce and Churchich (PMID:9183013) did show binding to denatured protein, Hip functions as a co-chaperone that stabilizes the Hsc70-substrate complex rather than as an independent unfolded protein handler. The appropriate replacement is GO:0044183 (protein folding chaperone), which captures the co-chaperone role in the protein folding machinery. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:9183013 The role of Hip as a molecular chaperone has been confirmed by its ability to strongly bind to the reduced, carboxymethylated form of alpha-lactalbumin. This interaction is specific for non-native domains since native alpha-lactalbumin fails to interact with Hip.
GO:0051087 protein-folding chaperone binding	IPI PMID:9528774 The carboxy-terminal domain of Hsc70 provides binding sites ...	ACCEPT	Summary: IPI annotation from Demand et al. (1998), who showed Hip interacts with Hsc70 (a protein-folding chaperone). This is essentially the same interaction as GO:0030544 (Hsp70 protein binding) but from a different perspective. Reason: Hip binds to Hsc70, which is a protein-folding chaperone. This annotation is complementary to GO:0030544 and captures the binding from the perspective of the chaperone partner type. Supporting Evidence: PMID:9528774 Hip interacts exclusively with the amino-terminal ATPase domain of Hsc70. file:rat/St13/St13-deep-research-falcon.md Hip binding and NEF binding are mutually exclusive
GO:0061084 negative regulation of protein refolding	IDA PMID:9183013 Characterization of the molecular-chaperone function of the ...	ACCEPT	Summary: IDA annotation from Bruce and Churchich (1997). The paper showed that Hip inhibited the refolding of alkaline phosphatase and malate dehydrogenase at near stoichiometric levels, and this inhibition could not be reversed by ATP addition. This is an in vitro observation with purified Hip alone; in the context of the Hsc70 system, Hip actually promotes protein folding by stabilizing the Hsc70-substrate complex. Reason: The experimental evidence clearly shows Hip inhibits protein refolding in vitro when acting alone (without Hsc70). This is a direct assay result that is correctly annotated. The annotation captures the intrinsic holdase-like activity of Hip, distinct from its positive role in the Hsc70 chaperone cycle. Supporting Evidence: PMID:9183013 Hip inhibited the refolding of alkaline phosphatase and malic dehydrogenase. Inhibition occurred at near stoichiometric levels of Hip and could not be reversed by the addition of ATP.
GO:0032991 protein-containing complex	IDA PMID:7585962 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hs...	MARK AS OVER ANNOTATED	Summary: IDA annotation from Hohfeld et al. (1995). Hip was identified as part of the Hsc70/Hsp40 chaperone complex. As noted above, GO:0032991 is extremely generic. Reason: Duplicate of the same overly generic term. GO:0032991 (protein-containing complex) is too broad to be informative. The specific complex membership is better captured by the protein-protein interaction annotations.
GO:0042802 identical protein binding	IDA PMID:7585962 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hs...	ACCEPT	Summary: IDA annotation from Hohfeld et al. (1995), who showed Hip forms homo-oligomers. Consistent with the IPI annotations for the same term. Reason: The original Hip paper demonstrated self-association as part of its characterization. This provides additional evidence for identical protein binding.
GO:0044877 protein-containing complex binding	IDA PMID:7585962 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hs...	ACCEPT	Summary: IDA annotation from Hohfeld et al. (1995). Hip binds to the Hsc70/Hsp40 complex. This is somewhat redundant with the more specific Hsp70 protein binding annotation. Reason: While somewhat redundant with GO:0030544 (Hsp70 protein binding), this annotation captures that Hip interacts with a multi-protein chaperone complex, not just isolated Hsc70. Hip binding to Hsc70 requires prior activation of the Hsc70 ATPase by Hsp40 (PMID:7585962), so the complex context is relevant. Supporting Evidence: PMID:7585962 One Hip oligomer binds the ATPase domains of at least two Hsc70 molecules dependent on activation of the Hsc70 ATPase by Hsp40.
GO:1903334 positive regulation of protein folding	IDA PMID:7585962 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hs...	ACCEPT	Summary: IDA annotation from Hohfeld et al. (1995). Hip stabilizes the ADP state of Hsc70 that has high affinity for substrate protein, thereby promoting the productive folding cycle. Through its own chaperone activity, it may contribute to Hsc70-substrate interactions. Reason: Hip positively regulates protein folding by stabilizing the Hsc70-substrate complex. This is the core biological process role of Hip in the context of the Hsc70 chaperone system, as distinct from its isolated holdase activity (GO:0061084). Supporting Evidence: PMID:7585962 Hip stabilizes the ADP state of Hsc70 that has a high affinity for substrate protein. Through its own chaperone activity, Hip may contribute to the interaction of Hsc70 with various target proteins. file:rat/St13/St13-deep-research-falcon.md stabilizing the ADP-bound conformation, Hip effectively increases the dwell time of Hsp70 on substrates, supporting folding/holding functions and counterbalancing NEF-driven acceleration of nucleotide exchange
GO:0019904 protein domain specific binding	IDA PMID:7585962 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hs...	ACCEPT	Summary: IDA annotation from Hohfeld et al. (1995). The original paper showed Hip binds the ATPase domain of Hsc70. Consistent with the more detailed domain mapping in PMID:8999928. Reason: The original characterization demonstrated domain-specific binding of Hip to the Hsc70 ATPase domain.
GO:0030544 Hsp70 protein binding	IDA PMID:7585962 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hs...	ACCEPT	Summary: IDA annotation from the original Hip paper (Hohfeld et al. 1995), demonstrating direct interaction between Hip and Hsc70. This is the core molecular function annotation for Hip. Reason: The definitive experimental demonstration of Hip binding to Hsc70, the core molecular function of this co-chaperone. Supporting Evidence: PMID:7585962 One Hip oligomer binds the ATPase domains of at least two Hsc70 molecules dependent on activation of the Hsc70 ATPase by Hsp40.

Gene Description

Existing Annotations Review

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References

Deep Research

Falcon

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