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.
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 proposed for obsoletion. Hip functions as a co-chaperone rather than as an independent chaperone that productively handles unfolded substrates. Reason: GO:0051082 (unfolded protein binding) is proposed for obsoletion. 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.

Core Functions

Hip/St13 functions as a co-chaperone that stabilizes the ADP-bound state of Hsc70, promoting substrate retention and enhancing the productive protein folding cycle. It binds the ATPase domain of Hsc70 via its TPR domain, attenuating the Hsp70 ATPase cycle and competing with nucleotide exchange factors.

Molecular Function:

Hsp70 protein binding

Directly Involved In:

protein folding positive regulation of protein folding

Cellular Locations:

cytosol

References

file:rat/St13/St13-deep-research-falcon.md

Falcon (Edison Scientific) deep research: Functional Annotation of St13 (Hip/ST13) in Rat (UniProt P50503)

Hip/ST13 is a co-chaperone that acts via protein-protein interaction and does not catalyze a chemical reaction, supporting a non-catalytic, Hsp70-binding core molecular function.

"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."
Hip binds the Hsp70 nucleotide-binding domain preferentially in the ADP-bound state, stabilizing the high substrate-affinity conformation and delaying client release.

"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**."
Hip binds the Hsp70 NBD through a central TPR domain, consistent with the domain-specific binding annotations.

"A **central TPR domain** that mediates Hsp70 NBD binding"
Rat Hip TPR region forms a structural bracket over the Hsp70 NBD, locking it in the ADP state and delaying substrate release.

"A rat Hip TPR-containing region forms a **structural “bracket” over the Hsp70 NBD**, obstructing NBD dynamics and thereby **locking Hsp70 in an ADP-bound state and delaying substrate release**."
Hip stabilizes the ADP-bound conformation, increasing Hsp70 dwell time on substrates and supporting folding, counterbalancing nucleotide exchange factors.

"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"
Hip and nucleotide exchange factors bind Hsp70 mutually exclusively; Hip competes with BAG1 and other NEFs.

"Hip binding and NEF binding are **mutually exclusive**"
Hip/ST13 is a cytosolic co-chaperone acting in the cytosolic Hsp70 cycle.

"Hip/ST13 is described as a **cytosolic** co-chaperone in reviews and mechanistic summaries, consistent with its role in the cytosolic Hsp70 cycle"
Hip has an N-terminal dimerization region involved in homo-oligomerization and forms a dimer in solution.

"An **N-terminal dimerization region** involved in homo-oligomerization"

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000121

RGD ISO annotations to rat from other mammalian species

PMID:21808025

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection.

PMID:23812373

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle.

PMID:7585962

Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle.

PMID:8999928

Characterization of functional domains of the eukaryotic co-chaperone Hip.

PMID:9183013

Characterization of the molecular-chaperone function of the heat-shock-cognate-70-interacting protein.

PMID:9528774

The carboxy-terminal domain of Hsc70 provides binding sites for a distinct set of chaperone cofactors.

Deep Research

Falcon

(St13-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 22 citations 2 artifacts 2026-06-01T02:22:36.478836

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000019 I have extracted Table 3, which lists the PDB IDs for Hip (4J8D/4J8E) and its complex with Hsp70 (4J8F), and Figure 2(h), which ill (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Functional Annotation of St13 (Hip/ST13) in Rat (Rattus norvegicus) — UniProt P50503

Executive summary

The rat gene St13 encodes Hsc70-interacting protein (Hip), a conserved cytosolic co-chaperone in the Hsp70/Hsc70 protein quality-control network. Hip’s primary molecular role is to bind the Hsp70 nucleotide-binding domain (NBD) in the ADP state and stabilize this high–substrate-affinity conformation, thereby slowing nucleotide (ADP) dissociation and delaying client release. This action functionally antagonizes Hsp70 nucleotide exchange factors (NEFs) and promotes productive folding/holding of client proteins. The most direct rat-specific evidence comes from rat Hip structures and Hip–Hsp70 complex structures (PDB 4J8D/4J8E/4J8F), which explain the “bracket” mechanism at atomic resolution. (karunanayake2021cytosolicproteinquality pages 8-10, li2013structureandfunction pages 121-125, karunanayake2021cytosolicproteinquality media 460eaeea)

1) Key concepts and definitions (current understanding)

1.1. What ST13/Hip is

Hip (ST13) is a co-chaperone: it modulates Hsp70/Hsc70 function through protein–protein interaction rather than catalyzing a chemical reaction. It is described as a ~41–43 kDa protein and forms a dimer in solution. (li2013structureandfunction pages 31-35, shi2007whatweknow pages 2-4)

1.2. Position in the Hsp70 cycle

The Hsp70 cycle alternates between an ATP-bound, low-substrate-affinity state and an ADP-bound, high-substrate-affinity state. Hip binds Hsp70’s NBD and stabilizes the ADP-bound state, preventing premature client release and thereby influencing substrate fate toward continued folding/retention. (shi2007whatweknow pages 1-2, karunanayake2021cytosolicproteinquality pages 8-10)

1.3. Domain architecture

Hip/ST13 is a modular co-chaperone with:
- An N-terminal dimerization region involved in homo-oligomerization
- A central TPR domain that mediates Hsp70 NBD binding
- Charged linker regions
- A C-terminal region containing GGMP repeats and a Sti1/DP-type motif, consistent with similarity to co-chaperone architectures in the Hsp70/Hsp90 network (Hip vs Hop distinctions are emphasized in structural work). (shi2007whatweknow pages 1-2, li2013structureandfunction pages 39-42, li2013structureandfunction pages 31-35)

2) Primary molecular function and mechanism (rat-relevant mechanistic evidence)

2.1. Structural mechanism (“bracket” model) — rat Hip evidence

A rat Hip TPR-containing region forms a structural “bracket” over the Hsp70 NBD, obstructing NBD dynamics and thereby locking Hsp70 in an ADP-bound state and delaying substrate release. This mechanism is supported by rat Hip structural studies and crystallographic complexes (PDB IDs 4J8D/4J8E for Hip and 4J8F for the Hip–Hsp70 complex). (karunanayake2021cytosolicproteinquality pages 8-10, karunanayake2021cytosolicproteinquality media 460eaeea)

The extracted figure/table region showing these PDB entries and the depicted interaction provides direct structural evidence for rat Hip’s binding mode to Hsp70. (karunanayake2021cytosolicproteinquality media 460eaeea, karunanayake2021cytosolicproteinquality media 599a47af)

2.2. Quantitative binding / state selectivity

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. (li2013structureandfunction pages 121-125)

2.3. Competition with nucleotide exchange factors (NEFs)

Hip binding and NEF binding are mutually exclusive, and NEFs generally bind more tightly (reported KD ~0.1 µM range) than Hip (reported ~10 µM range), providing a quantitative framework for how Hip tunes Hsp70 cycle kinetics rather than acting as a canonical NEF. (li2013structureandfunction pages 121-125)

3) Biological processes, pathways, and cellular localization

3.1. Pathway context: cytosolic proteostasis / protein quality control

Hip is embedded in the cytosolic Hsp70 protein quality-control machinery, helping balance folding, stabilization, and downstream triage decisions (folding vs degradation) by controlling the kinetics of client release from Hsp70. (karunanayake2021cytosolicproteinquality pages 8-10)

3.2. Localization

Hip/ST13 is described as a cytosolic co-chaperone in reviews and mechanistic summaries, consistent with its role in the cytosolic Hsp70 cycle and with its historical identification in cytosolic steroid-receptor chaperone complexes. (shi2007whatweknow pages 1-2, li2013structureandfunction pages 31-35)

Limitation (rat-specific localization): within the retrieved full-text corpus, direct rat cell/tissue imaging or fractionation studies for St13/Hip localization were not recovered; thus localization is supported primarily by functional context and conserved mammalian cell biology rather than rat-specific microscopy. (shi2007whatweknow pages 1-2, li2013structureandfunction pages 31-35)

4) Interaction partners and functional network placement

Hip participates in a broader co-chaperone network that includes positive and negative regulators of Hsp70:
- Positive functional relationships in folding include Hsp40/DNAJ proteins and cooperation/coordination with other co-chaperones
- Antagonistic/competitive relationships include BAG1, a factor that stimulates ADP dissociation and promotes substrate release; Hip can compete for NBD binding and thereby oppose BAG1-mediated nucleotide exchange. (shi2007whatweknow pages 2-4)

Hip also has been reported to associate with specific client/protein systems in mammalian contexts, including receptor systems (e.g., CXCR2 regulation and trafficking) and aggregation-prone proteins (see below). (shi2007whatweknow pages 6-7)

5) Disease-relevant functional evidence (ortholog-informed; not rat-specific)

5.1. Proteostasis in neurodegeneration models

A mechanistic study in the Parkinson’s disease context reported that Hip (ST13) can stabilize the Hsp70/α-synuclein complex and prevent Hsp70 co-aggregation with α-synuclein in vitro; the authors argued decreased Hip expression could facilitate Hsp70 depletion by amyloidogenic substrates, impairing proteostasis. (Dec 2009; https://doi.org/10.1038/emboj.2009.298) (roodveldt2009chaperoneproteostasisin pages 1-1, roodveldt2009chaperoneproteostasisin pages 12-13)

A review summarized reports of altered ST13 expression in colorectal cancer and discussion of tumor-suppressor claims, but also stressed that evidence was incomplete and that physiological/in vivo evidence was limited at the time. (Mar 2007; https://doi.org/10.1631/jzus.2007.b0170) (shi2007whatweknow pages 4-6)

6) Recent developments (prioritizing 2023–2024) and real-world implementations

6.1. 2024: Bioprocessing analytics — AAV vector purification residual host cell proteins

In a 2024 Molecular Therapy – Methods & Clinical Development study on proteomic analysis of residual host cell proteins across AAV affinity chromatography, Hsc70-interacting protein (ST13) was reported among proteins present at notably high amounts compared with other host cell proteins (in the context of process analytics and impurity profiling). (Dec 2024; https://doi.org/10.1016/j.omtm.2024.101383) (leibiger2024quantitativeproteomicanalysis pages 9-10)

Interpretation: this does not change Hip’s mechanistic annotation, but it demonstrates a current, real-world implementation where ST13/Hip is measured and monitored in industrial-quality control proteomics workflows. (leibiger2024quantitativeproteomicanalysis pages 9-10)

6.2. 2023: Human developmental regulatory genomics mention

A 2023 Nature Communications study mapping eQTLs in fetal-like pancreatic progenitor cells mentions ST13 (Hsc70-interacting protein) in the context of candidate causal genes and biological interpretation of regulatory variation (not as a mechanistic Hip paper). (Oct 2023; https://doi.org/10.1038/s41467-023-42560-4) (evidence of mention retrieved as part of search results context; mechanistic details were not extracted in the current evidence set) (leibiger2024quantitativeproteomicanalysis pages 9-10)

Scope note: This 2023 paper contributes to contemporary relevance (genomics/association context) but does not replace the established structural mechanism for Hip’s function in the Hsp70 cycle. (li2013structureandfunction pages 121-125, karunanayake2021cytosolicproteinquality pages 8-10)

7) Key statistics and data points (from retrieved studies)

Hip binds Hsp70 preferentially in the ADP-bound state with KD ≈ 8 µM; binding to apo Hsp70 is weaker (KD ≈ 51 µM); ATP-bound binding was not detected under the cited conditions. (li2013structureandfunction pages 121-125)
Hip is described as present at roughly ~1 µM in reticulocyte lysate (order-of-magnitude cellular abundance estimate in classic biochemical systems). (li2013structureandfunction pages 31-35)
Rat structural resources: Hip and complex PDB IDs include 4J8D, 4J8E, 4J8F (rat Hip; Hip–Hsp70 complex). (karunanayake2021cytosolicproteinquality pages 8-10, karunanayake2021cytosolicproteinquality media 460eaeea)

8) Expert interpretation and synthesis (authoritative analysis)

Across authoritative reviews and mechanistic structural work, the most consistent interpretation is that Hip/ST13 is an attenuator/timer of the Hsp70 cycle: by 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. This “kinetic tuning” model is strongly supported by rat structural data that directly show Hip restraining NBD motion (“bracket”) and by quantitative affinity differences for ADP/apo/ATP states. (li2013structureandfunction pages 121-125, karunanayake2021cytosolicproteinquality pages 8-10, karunanayake2021cytosolicproteinquality media 460eaeea)

Evidence summary table

Aspect	Key statement	Organism relevance	Main evidence source with citation id(s)	Publication year	DOI/URL
Identity / synonyms	UniProt P50503 corresponds to Rattus norvegicus St13, encoding Hsc70-interacting protein (Hip); literature also uses ST13, Hip, and p48. This matches the requested rat co-chaperone rather than an unrelated ST13 symbol.	Rat-focused; identity supported by rat Hip structural/biochemical literature and conserved mammalian nomenclature	Shi et al. review identifying ST13 as Hip/p48 and noting strong rat-human homology; rat Hip structural study summary (shi2007whatweknow pages 1-2, li2013structureandfunction pages 31-35, karunanayake2021cytosolicproteinquality pages 8-10)	2007, 2013, 2021	https://doi.org/10.1631/jzus.2007.b0170 ; https://doi.org/10.1038/nsmb.2608 ; https://doi.org/10.1177/1535370221999812
Domains	Hip/ST13 is a multidomain co-chaperone with an N-terminal dimerization region (Hip_N), a central TPR domain that mediates Hsp70 binding, acidic/charged linker segments, and a C-terminal GGMP / STI1-HOP_DP-like region with DP motifs.	Domain architecture is conserved across mammalian Hip proteins; rat structural work directly supports TPR-based binding	Domain/mechanistic reviews and rat Hip structure summaries (shi2007whatweknow pages 1-2, li2013structureandfunction pages 39-42, li2013structureandfunction pages 31-35, karunanayake2021cytosolicproteinquality pages 8-10)	2007, 2013, 2021	https://doi.org/10.1631/jzus.2007.b0170 ; https://doi.org/10.1038/nsmb.2608 ; https://doi.org/10.1177/1535370221999812
Molecular function	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.	Broadly conserved in eukaryotes; directly relevant to rat because rat Hip structures define the mechanism	Reviews and structural synthesis describing Hip as a positive Hsp70 co-factor (shi2007whatweknow pages 1-2, li2013structureandfunction pages 31-35, karunanayake2021cytosolicproteinquality pages 8-10, shi2007whatweknow pages 2-4)	2007, 2013, 2021	https://doi.org/10.1631/jzus.2007.b0170 ; https://doi.org/10.1038/nsmb.2608 ; https://doi.org/10.1177/1535370221999812
Mechanism in Hsp70 cycle	Hip binds the Hsp70 nucleotide-binding domain (NBD) preferentially in the ADP-bound state, forms a TPR-domain “bracket” over the NBD, restrains NBD dynamics, slows ADP dissociation, and thereby delays substrate release. Hip and nucleotide-exchange factors bind mutually exclusively.	Mechanistic core comes from rat Hip crystal structures and mammalian biochemistry; highly applicable to rat P50503	Rat Hip/Hsp70 structural evidence and mechanistic reviews (karunanayake2021cytosolicproteinquality pages 8-10, li2013structureandfunction pages 121-125)	2013, 2021	https://doi.org/10.1038/nsmb.2608 ; https://doi.org/10.1177/1535370221999812
Interaction partners	Established partners include Hsc70/Hsp70, functional interplay with Hsp40/DNAJ proteins, competition with BAG1 and other NEFs, cooperation/contrast with HOP/STI1 and CHIP/STUB1, and in some contexts direct association with substrates such as CXCR2 and aggregation-prone proteins such as α-synuclein.	Mostly mammalian rather than rat-specific interaction evidence, but consistent with rat Hip sequence/domain conservation	Reviews and disease-mechanism papers (shi2007whatweknow pages 2-4, shi2007whatweknow pages 6-7, li2013structureandfunction pages 39-42, li2013structureandfunction pages 31-35)	2007, 2009, 2013	https://doi.org/10.1631/jzus.2007.b0170 ; https://doi.org/10.1038/emboj.2009.298 ; https://doi.org/10.1038/nsmb.2608
Localization	ST13/Hip is best supported as a cytosolic protein acting in the cytosolic Hsp70 protein-quality-control network and in cytosolic steroid-receptor maturation complexes.	Primarily inferred from mammalian cell biology/reviews; no strong rat-specific subcellular localization paper was recovered here	Cytosolic designation and receptor-complex context from reviews (shi2007whatweknow pages 1-2, li2013structureandfunction pages 31-35, shi2007whatweknow pages 2-4)	2007, 2013	https://doi.org/10.1631/jzus.2007.b0170 ; https://doi.org/10.1038/nsmb.2608
Pathways / processes	Principal pathway assignment is cytosolic proteostasis / protein quality control, especially the Hsp70 chaperone cycle controlling folding, refolding, and substrate fate. Additional implicated processes include steroid receptor maturation and suppression of toxic protein aggregation.	Conserved mammalian pathway role; rat relevance strong because rat Hip defines the structural mechanism within the Hsp70 cycle	Hsp70 network review and Hip studies (shi2007whatweknow pages 4-6, li2013structureandfunction pages 39-42, karunanayake2021cytosolicproteinquality pages 8-10)	2007, 2013, 2021	https://doi.org/10.1631/jzus.2007.b0170 ; https://doi.org/10.1038/nsmb.2608 ; https://doi.org/10.1177/1535370221999812
Disease links	Hip/ST13 has been discussed in neurodegeneration because it stabilizes Hsp70–α-synuclein complexes and can reduce toxic aggregation; older literature also discussed possible tumor-suppressor / colorectal cancer relevance, though evidence was considered incomplete and context-dependent.	Disease links are mostly from human/cell-model or non-rat systems; should be treated as ortholog-informed rather than rat-specific function	Parkinson’s disease proteostasis study and ST13 review (roodveldt2009chaperoneproteostasisin pages 1-1, shi2007whatweknow pages 2-4, roodveldt2009chaperoneproteostasisin pages 12-13, shi2007whatweknow pages 4-6)	2007, 2009	https://doi.org/10.1631/jzus.2007.b0170 ; https://doi.org/10.1038/emboj.2009.298
2023–2024 developments / applications	Direct 2023–2024 rat St13 functional papers were not recovered. Recent mentions are mainly omics/proteomics contexts rather than mechanism papers: ST13 appeared among retained host-cell proteins in AAV purification workflows, and a 2023 developmental-genetics study cited ST13 as an Hsc70-interacting protein candidate in pancreas-related regulatory analyses. These are useful as implementation/biomarker contexts but do not materially revise core function.	Recent evidence is non-rat mechanistic and mostly human/bioprocessing context; limited direct applicability beyond expression/assay relevance	2024 AAV host-cell protein proteomics and 2023 eQTL study mention ST13 (leibiger2024quantitativeproteomicanalysis pages 9-10)	2023, 2024	https://doi.org/10.1016/j.omtm.2024.101383 ; https://doi.org/10.1038/s41467-023-42560-4
Quantitative data	Reported quantitative features include: Hip binds ADP-Hsp70 preferentially with KD ≈ 8 µM, weaker binding to apo-Hsp70 (KD ≈ 51 µM), and no detectable binding to ATP-Hsp70 under the cited conditions; competing NEFs bind more tightly (~0.1 µM). Hip is described as a ~41–43 kDa protein, dimeric in solution, with estimated abundance around ~1 µM in reticulocyte lysate. Structural resources include rat Hip/Hsp70 complex entries 4J8D, 4J8E, 4J8F.	Quantitative binding/mechanistic data derive from mammalian/rat Hip structural biochemistry and are highly relevant to rat P50503	Structural/biophysical analyses and review synthesis (li2013structureandfunction pages 121-125, li2013structureandfunction pages 31-35, karunanayake2021cytosolicproteinquality pages 8-10)	2013, 2021	https://doi.org/10.1038/nsmb.2608 ; https://doi.org/10.1177/1535370221999812

Table: This table summarizes the verified identity, domain architecture, molecular mechanism, localization, pathways, disease links, recent developments, and quantitative evidence for rat St13/HIP (UniProt P50503). It distinguishes rat-direct evidence from broader mammalian ortholog evidence so the final annotation can stay specific and well-supported.

Limitations and evidence gaps (important for correct annotation)

UniProt-page verification: The tools did not provide direct UniProt P50503 record text; identity confirmation therefore relies on concordant rat Hip/ST13 literature (rat structures; ST13=Hip synonymy) rather than directly citing UniProt fields. (li2013structureandfunction pages 31-35, karunanayake2021cytosolicproteinquality pages 8-10)
Rat-specific expression/localization/phenotypes: Within retrieved full texts, rat tissue expression atlases, knockout/knockdown phenotypes, or microscopy localization studies were not identified. As a result, pathway/localization statements are supported primarily by conserved mechanistic context rather than rat-specific in vivo experiments. (shi2007whatweknow pages 1-2, li2013structureandfunction pages 31-35)

Key references (with publication dates and URLs)

Karunanayake & Page. Experimental Biology and Medicine (Mar 2021). Cytosolic Hsp70 co-chaperone network; includes rat Hip structure and PDB IDs. https://doi.org/10.1177/1535370221999812 (karunanayake2021cytosolicproteinquality pages 8-10, karunanayake2021cytosolicproteinquality media 460eaeea)
Li, Hartl, Bracher. Nature Structural & Molecular Biology (Jun 2013). Hip structure/function; quantitative binding and ADP-state stabilization mechanism. https://doi.org/10.1038/nsmb.2608 (li2013structureandfunction pages 121-125, li2013structureandfunction pages 31-35)
Roodveldt et al. EMBO Journal (Dec 2009). Hip stabilizes Hsp70/α-synuclein complex; proteostasis implications. https://doi.org/10.1038/emboj.2009.298 (roodveldt2009chaperoneproteostasisin pages 1-1, roodveldt2009chaperoneproteostasisin pages 12-13)
Shi et al. Journal of Zhejiang University SCIENCE B (Mar 2007). Review of ST13/Hip domains, co-chaperone roles, steroid receptor and cancer discussions. https://doi.org/10.1631/jzus.2007.b0170 (shi2007whatweknow pages 1-2, shi2007whatweknow pages 2-4)
Leibiger et al. Molecular Therapy – Methods & Clinical Development (Dec 2024). ST13 as high-abundance residual host cell protein in AAV affinity purification analytics. https://doi.org/10.1016/j.omtm.2024.101383 (leibiger2024quantitativeproteomicanalysis pages 9-10)

References

(karunanayake2021cytosolicproteinquality pages 8-10): Chamithi Karunanayake and Richard C Page. Cytosolic protein quality control machinery: interactions of hsp70 with a network of co-chaperones and substrates. Experimental Biology and Medicine, 246:1419-1434, Mar 2021. URL: https://doi.org/10.1177/1535370221999812, doi:10.1177/1535370221999812. This article has 20 citations and is from a peer-reviewed journal.
(li2013structureandfunction pages 121-125): Zhuo Li, F Ulrich Hartl, and Andreas Bracher. Structure and function of hip, an attenuator of the hsp70 chaperone cycle. Nature Structural &Molecular Biology, 20:929-935, Jun 2013. URL: https://doi.org/10.1038/nsmb.2608, doi:10.1038/nsmb.2608. This article has 97 citations.
(karunanayake2021cytosolicproteinquality media 460eaeea): Chamithi Karunanayake and Richard C Page. Cytosolic protein quality control machinery: interactions of hsp70 with a network of co-chaperones and substrates. Experimental Biology and Medicine, 246:1419-1434, Mar 2021. URL: https://doi.org/10.1177/1535370221999812, doi:10.1177/1535370221999812. This article has 20 citations and is from a peer-reviewed journal.
(li2013structureandfunction pages 31-35): Zhuo Li, F Ulrich Hartl, and Andreas Bracher. Structure and function of hip, an attenuator of the hsp70 chaperone cycle. Nature Structural &Molecular Biology, 20:929-935, Jun 2013. URL: https://doi.org/10.1038/nsmb.2608, doi:10.1038/nsmb.2608. This article has 97 citations.
(shi2007whatweknow pages 2-4): Zheng-zheng Shi, Jia-wei Zhang, and Shu Zheng. What we know about st13, a co-factor of heat shock protein, or a tumor suppressor? Journal of Zhejiang University SCIENCE B, 8:170-176, Mar 2007. URL: https://doi.org/10.1631/jzus.2007.b0170, doi:10.1631/jzus.2007.b0170. This article has 59 citations.
(shi2007whatweknow pages 1-2): Zheng-zheng Shi, Jia-wei Zhang, and Shu Zheng. What we know about st13, a co-factor of heat shock protein, or a tumor suppressor? Journal of Zhejiang University SCIENCE B, 8:170-176, Mar 2007. URL: https://doi.org/10.1631/jzus.2007.b0170, doi:10.1631/jzus.2007.b0170. This article has 59 citations.
(li2013structureandfunction pages 39-42): Zhuo Li, F Ulrich Hartl, and Andreas Bracher. Structure and function of hip, an attenuator of the hsp70 chaperone cycle. Nature Structural &Molecular Biology, 20:929-935, Jun 2013. URL: https://doi.org/10.1038/nsmb.2608, doi:10.1038/nsmb.2608. This article has 97 citations.
(karunanayake2021cytosolicproteinquality media 599a47af): Chamithi Karunanayake and Richard C Page. Cytosolic protein quality control machinery: interactions of hsp70 with a network of co-chaperones and substrates. Experimental Biology and Medicine, 246:1419-1434, Mar 2021. URL: https://doi.org/10.1177/1535370221999812, doi:10.1177/1535370221999812. This article has 20 citations and is from a peer-reviewed journal.
(shi2007whatweknow pages 6-7): Zheng-zheng Shi, Jia-wei Zhang, and Shu Zheng. What we know about st13, a co-factor of heat shock protein, or a tumor suppressor? Journal of Zhejiang University SCIENCE B, 8:170-176, Mar 2007. URL: https://doi.org/10.1631/jzus.2007.b0170, doi:10.1631/jzus.2007.b0170. This article has 59 citations.
(roodveldt2009chaperoneproteostasisin pages 1-1): Cintia Roodveldt, Carlos W Bertoncini, August Andersson, Annemieke T van der Goot, Shang-Te Hsu, Rafael Fernández-Montesinos, Jannie de Jong, Tjakko J van Ham, Ellen A Nollen, David Pozo, John Christodoulou, and Christopher M Dobson. Chaperone proteostasis in parkinson's disease: stabilization of the hsp70/α‐synuclein complex by hip. The EMBO Journal, 28:3758-3770, Dec 2009. URL: https://doi.org/10.1038/emboj.2009.298, doi:10.1038/emboj.2009.298. This article has 151 citations.
(roodveldt2009chaperoneproteostasisin pages 12-13): Cintia Roodveldt, Carlos W Bertoncini, August Andersson, Annemieke T van der Goot, Shang-Te Hsu, Rafael Fernández-Montesinos, Jannie de Jong, Tjakko J van Ham, Ellen A Nollen, David Pozo, John Christodoulou, and Christopher M Dobson. Chaperone proteostasis in parkinson's disease: stabilization of the hsp70/α‐synuclein complex by hip. The EMBO Journal, 28:3758-3770, Dec 2009. URL: https://doi.org/10.1038/emboj.2009.298, doi:10.1038/emboj.2009.298. This article has 151 citations.
(shi2007whatweknow pages 4-6): Zheng-zheng Shi, Jia-wei Zhang, and Shu Zheng. What we know about st13, a co-factor of heat shock protein, or a tumor suppressor? Journal of Zhejiang University SCIENCE B, 8:170-176, Mar 2007. URL: https://doi.org/10.1631/jzus.2007.b0170, doi:10.1631/jzus.2007.b0170. This article has 59 citations.
(leibiger2024quantitativeproteomicanalysis pages 9-10): Thomas M. Leibiger, Lie Min, and Kelvin H. Lee. Quantitative proteomic analysis of residual host cell protein retention across adeno-associated virus affinity chromatography. Dec 2024. URL: https://doi.org/10.1016/j.omtm.2024.101383, doi:10.1016/j.omtm.2024.101383. This article has 11 citations.

Artifacts

Edison artifact artifact-00

Citations

li2013structureandfunction pages 121-125
karunanayake2021cytosolicproteinquality pages 8-10
shi2007whatweknow pages 2-4
shi2007whatweknow pages 6-7
shi2007whatweknow pages 4-6
leibiger2024quantitativeproteomicanalysis pages 9-10
li2013structureandfunction pages 31-35
shi2007whatweknow pages 1-2
li2013structureandfunction pages 39-42
roodveldt2009chaperoneproteostasisin pages 1-1
roodveldt2009chaperoneproteostasisin pages 12-13
https://doi.org/10.1038/emboj.2009.298
https://doi.org/10.1631/jzus.2007.b0170
https://doi.org/10.1016/j.omtm.2024.101383
https://doi.org/10.1038/s41467-023-42560-4
https://doi.org/10.1038/nsmb.2608
https://doi.org/10.1177/1535370221999812
https://doi.org/10.1177/1535370221999812,
https://doi.org/10.1038/nsmb.2608,
https://doi.org/10.1631/jzus.2007.b0170,
https://doi.org/10.1038/emboj.2009.298,
https://doi.org/10.1016/j.omtm.2024.101383,

📚 Additional Documentation

Bioreason Rl Predictions

(St13-bioreason-rl-predictions.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:03 AM

Organism: Rattus norvegicus

Sequence:

MDPRKVSELRAFVKMCRQDPSVLHTEEMRFLREWVESMGGKVPPATHKAKSEENTKEEKRDKTTEDNIKTEEPSSEESDLEIDNEGVIEADTDAPQEMGDENAEITEAMMDEANEKKGAAIDALNDGELQKAIDLFTDAIKLNPRLAILYAKRASVFVKLQKPNAAIRDCDRAIEINPDSAQPYKWRGKAHRLLGHWEEAARDLALACKLDYDEDASAMLREVQPRAQKIAEHRRKYERKREEREIKERIERVKKAREEHEKAQREEEARRQSGSQFGSFPGGFPGGMPGNFPGGMPGMGGAMPGMAGMPGLNEILSDPEVLAAMQDPEVMVAFQDVAQNPSNMSKYQNNPKVMNLISKLSAKFGGHS

Thinking Trace

I begin with the domain architecture. The N-terminus carries IPR034649 (Hsp70-interacting protein, N-terminal, residues 2–43), a hallmark module that binds and regulates Hsp70/Hsc70 systems. Mid-chain, IPR011990 (Tetratricopeptide-like helical domain superfamily, residues 73–247) forms an extended helical scaffold, within which IPR019734 (Tetratricopeptide repeat, residues 113–214) builds a canonical TPR groove used for high-affinity docking of chaperones and cochaperones. The C-terminal half contains IPR041243 (STI1/HOP, DP domain, residues 314–360) and IPR006636 (Heat shock chaperonin-binding domain, residues 318–357). This tandem arrangement—N-terminal Hsp70-interacting region, central TPR platform, and C-terminal DP/chaperonin-binding cassette—creates a bipartite cochaperone architecture specialized for capturing, stabilizing, and coordinating Hsp70/Hsc70 and chaperonin cycles.

This architecture dictates molecular function. The N-terminal Hsp70-interacting module and the TPR-based central scaffold cooperatively generate a high-avidity surface for chaperone engagement, establishing a strong case for GO:0051082 unfolded protein binding through chaperone-mediated capture and release. The DP domain together with the heat shock chaperonin-binding cassette further stabilizes client transfer between Hsp70 systems and chaperonins, reinforcing a role as a cochaperone that buffers exposed hydrophobic surfaces on non-native substrates.

From this molecular activity, the biological process follows. By buffering non-native substrates and coordinating their handoff among Hsp70 and chaperonin machineries, the protein promotes proteostasis—formally captured by GO:0006457 protein folding and GO:0042026 protein refolding. Its TPR-mediated assembly of multi-chaperone complexes accelerates folding and prevents aggregation, especially under conditions that transiently increase client load.

Cellular location is implied by the soluble, helical-repeat architecture lacking transmembrane segments or secretion signals, pointing to a soluble compartment. Chaperone triage and refolding predominantly occur in the cytoplasm, supporting GO:0005737 cytoplasm. The presence of soluble chaperone systems that buffer misfolded species near nuclear material and ribosome-rich regions also accommodates shuttling near the nucleus; thus transient perinuclear residency is plausible alongside its core cytoplasmic role.

Mechanistically, the protein likely nucleates higher-order folding assemblies. The N-terminal Hsp70-interacting region recruits Hsp70/Hsc70, the TPR core aligns cochaperones and clients, and the C-terminal DP/chaperonin-binding cassette stabilizes transitions into or out of chaperonin cycles. I hypothesize it bridges Hsp70/Hsc70 with Hsp90 and the TRiC/CCT pathway to funnel clients toward native states. Predicted partners include cytosolic Hsp70s (e.g., HSPA8), Hsp90 isoforms, and the CCT/TRiC complex; together they form a dynamic hub that prevents aggregation and drives refolding in the cytoplasm with possible perinuclear engagement.

Functional Summary

A soluble cochaperone that organizes cytoplasmic protein quality-control assemblies. It uses an Hsp70-recognition module and a central TPR scaffold to capture non-native client proteins and assemble multi-chaperone complexes, thereby preventing aggregation and promoting refolding. Its C-terminal DP/chaperonin-binding cassette coordinates handoff between Hsp70/Hsc70 systems and the chaperonin pathway, operating primarily in the cytoplasm with potential perinuclear engagement as it triages misfolded substrates.

UniProt Summary

Prevents aggregation of denatured proteins.

InterPro Domains

Hsp70-interacting protein, N-terminal (IPR034649, domain) — residues 2-43
Tetratricopeptide-like helical domain superfamily (IPR011990, homologous_superfamily) — residues 73-247
Tetratricopeptide repeat (IPR019734, repeat) — residues 113-214
STI1/HOP, DP domain (IPR041243, domain) — residues 314-360
Heat shock chaperonin-binding (IPR006636, domain) — residues 318-357

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), small molecule binding (GO:0036094), heterocyclic compound binding (GO:1901363), protein-containing complex binding (GO:0044877), ion binding (GO:0043167), organic cyclic compound binding (GO:0097159), carbohydrate derivative binding (GO:0097367), protein binding (GO:0005515), heat shock protein binding (GO:0031072), nucleoside phosphate binding (GO:1901265), chaperone binding (GO:0051087), unfolded protein binding (GO:0051082), anion binding (GO:0043168), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein domain specific binding (GO:0019904), Hsp70 protein binding (GO:0030544), purine nucleotide binding (GO:0017076), adenyl nucleotide binding (GO:0030554)

Biological Process: biological_process (GO:0008150), regulation of biological process (GO:0050789), cellular process (GO:0009987), negative regulation of biological process (GO:0048519), biological regulation (GO:0065007), negative regulation of cellular process (GO:0048523), protein folding (GO:0006457), regulation of cellular process (GO:0050794), 'de novo' protein folding (GO:0006458), chaperone-mediated protein folding (GO:0061077), 'de novo' post-translational protein folding (GO:0051084), chaperone cofactor-dependent protein refolding (GO:0051085)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), protein-containing complex (GO:0032991), cytoplasm (GO:0005737), cytosol (GO:0005829), intracellular anatomical structure (GO:0005622)

Generated by BioReason

Bioreason Rl Review

(St13-bioreason-rl-review.md)

BioReason-Pro RL Review: St13 (rat)

Source: St13-bioreason-rl-predictions.md

Correctness: 4/5
Completeness: 4/5

Functional Summary Review

The functional summary states:

A soluble cochaperone that organizes cytoplasmic protein quality-control assemblies. It uses an Hsp70-recognition module and a central TPR scaffold to capture non-native client proteins and assemble multi-chaperone complexes, thereby preventing aggregation and promoting refolding. Its C-terminal DP/chaperonin-binding cassette coordinates handoff between Hsp70/Hsc70 systems and the chaperonin pathway, operating primarily in the cytoplasm with potential perinuclear engagement as it triages misfolded substrates.

This is largely accurate and well-aligned with the curated review. The ai-review.yaml confirms protein folding (GO:0006457), Hsp70 protein binding (GO:0030544), cytoplasm (GO:0005737), unfolded protein binding (GO:0051082), and chaperone cofactor-dependent protein refolding (GO:0051085). The curated description explicitly notes that Hip/St13 stabilizes the ADP-bound state of Hsc70 and competes with BAG-1 for binding to the Hsc70 ATPase domain.

BioReason correctly identifies the N-terminal Hsp70-interacting module (IPR034649), the TPR scaffold, and the C-terminal DP/chaperonin-binding domains. The description of organizing multi-chaperone complexes is accurate.

One minor issue: BioReason describes St13 as capturing "non-native client proteins" via "unfolded protein binding." The curated review notes that the curated IBA for unfolded protein binding is present, and the protein does have its own chaperone activity (PMID:9183013), but the primary role is as a co-chaperone that modulates Hsc70's ATPase cycle rather than independently binding unfolded substrates. The nuance of St13 stabilizing the ADP-bound state of Hsc70 (slowing nucleotide exchange to enhance substrate affinity) is not captured. Instead, BioReason presents it more as an independent chaperone than a regulatory co-factor.

The curated review also notes protein dimerization activity (GO:0046983) as over-annotated -- St13 forms tetramers via its N-terminal domain, which is structural rather than functional. BioReason does not mention self-association.

Comparison with interpro2go:

The interpro2go annotation for St13 is protein dimerization activity (GO:0046983), which the curated review marks as MARK_AS_OVER_ANNOTATED. BioReason does not recapitulate this error -- it correctly focuses on the cochaperone function rather than self-association, representing an improvement over interpro2go in this case.

Notes on thinking trace

The trace is well-organized and correctly maps the domain architecture to cochaperone function. The hypothesized bridging between Hsp70/Hsc70 and Hsp90/TRiC/CCT pathways is an interesting inference, though the direct evidence for St13 coordinating TRiC/CCT engagement is limited. The mention of HSPA8 as a specific predicted partner is correct and matches the curated literature (PMID:7585962).

📄 View Raw YAML

id: P50503
gene_symbol: St13
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:10116
  label: Rattus norvegicus
description: >-
  Hsc70-interacting protein (Hip/ST13) is a TPR-containing co-chaperone that
  regulates the Hsp70 chaperone cycle. Hip forms homo-oligomers (tetramers) and
  binds the ATPase domain of Hsc70, stabilizing the ADP-bound state which has
  high affinity for substrate proteins (PMID:7585962). By slowing ADP
  dissociation from Hsc70, Hip attenuates active cycling and enhances
  aggregation prevention (PMID:23812373). Hip possesses its own chaperone
  activity, binding non-native proteins but unable to facilitate their refolding
  independently (PMID:9183013). Hip competes with BAG-1 (a nucleotide exchange
  factor) for binding to the Hsc70 ATPase domain (PMID:9528774).
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:7585962
        supporting_text: >-
          The Hsc70-interacting protein Hip, a tetratricopeptide repeat protein,
          participates in the regulation of the eukaryotic 70 kDa heat shock cognate
          Hsc70.
      - reference_id: file:rat/St13/St13-deep-research-falcon.md
        supporting_text: |-
          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.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:7585962
        supporting_text: >-
          One Hip oligomer binds the ATPase domains of at least two Hsc70 molecules
          dependent on activation of the Hsc70 ATPase by Hsp40.
      - reference_id: file:rat/St13/St13-deep-research-falcon.md
        supporting_text: |-
          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**.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation from UniProt subcellular location mapping. UniProt
      annotates St13 to the cytoplasm. Consistent with IDA evidence for
      cytosol localization (PMID:7585962).
    action: ACCEPT
    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).
- term:
    id: GO:0046983
    label: protein dimerization activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21808025
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23812373
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:23812373
        supporting_text: >-
          Here we present crystal structures of the dimerization domain and the
          tetratricopeptide repeat (TPR) domain of rat Hip.
      - reference_id: file:rat/St13/St13-deep-research-falcon.md
        supporting_text: |-
          An **N-terminal dimerization region** involved in homo-oligomerization
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:7585962
  review:
    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.
    action: ACCEPT
    reason: >-
      Cytosol localization is well-established from the original identification
      of Hip as a cytosolic co-chaperone. This is a core cellular component
      annotation.
    supported_by:
      - reference_id: PMID:7585962
        supporting_text: >-
          The Hsc70-interacting protein Hip, a tetratricopeptide repeat protein,
          participates in the regulation of the eukaryotic 70 kDa heat shock cognate
          Hsc70.
      - reference_id: file:rat/St13/St13-deep-research-falcon.md
        supporting_text: |-
          Hip/ST13 is described as a **cytosolic** co-chaperone in reviews and mechanistic summaries, consistent with its role in the cytosolic Hsp70 cycle
- term:
    id: GO:0009617
    label: response to bacterium
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    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.
    action: UNDECIDED
    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.
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IDA
  original_reference_id: PMID:8999928
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:8999928
        supporting_text: >-
          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.
      - reference_id: file:rat/St13/St13-deep-research-falcon.md
        supporting_text: |-
          A **central TPR domain** that mediates Hsp70 NBD binding
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:9528774
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:9528774
        supporting_text: >-
          Hip interacts exclusively with the amino-terminal ATPase domain of
          Hsc70... Hsc70 possesses separate nonoverlapping binding sites for
          Hsp40, Hip, and Hop.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IPI
  original_reference_id: PMID:9528774
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct physical interaction evidence for Hip binding to Hsc70,
      consistent with multiple other lines of evidence.
    supported_by:
      - reference_id: PMID:9528774
        supporting_text: >-
          Hip interacts exclusively with the amino-terminal ATPase domain of Hsc70.
- term:
    id: GO:0032564
    label: dATP binding
  evidence_type: IDA
  original_reference_id: PMID:9183013
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:9183013
        supporting_text: >-
          fluorescence measurements indicated that the chaperone recognizes
          anthraniloyl-dATP, anthraniloyl-ADP, and 2'-O-trinitrophenyl-ATP.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:9528774
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:8999928
  review:
    summary: >-
      IPI annotation from Irmer and Hohfeld (1997), who identified the
      N-terminal homo-oligomerization domain of Hip.
    action: ACCEPT
    reason: >-
      The study directly demonstrates self-association of Hip through its
      N-terminal domain, supporting identical protein binding.
    supported_by:
      - reference_id: PMID:8999928
        supporting_text: >-
          a domain required for homo-oligomerization was identified at the
          extreme amino terminus of Hip.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:9183013
  review:
    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
      proposed for obsoletion. Hip functions as a co-chaperone rather than
      as an independent chaperone that productively handles unfolded substrates.
    action: MODIFY
    reason: >-
      GO:0051082 (unfolded protein binding) is proposed for obsoletion.
      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_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:9183013
        supporting_text: >-
          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.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:9528774
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:9528774
        supporting_text: >-
          Hip interacts exclusively with the amino-terminal ATPase domain of Hsc70.
      - reference_id: file:rat/St13/St13-deep-research-falcon.md
        supporting_text: |-
          Hip binding and NEF binding are **mutually exclusive**
- term:
    id: GO:0061084
    label: negative regulation of protein refolding
  evidence_type: IDA
  original_reference_id: PMID:9183013
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:9183013
        supporting_text: >-
          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.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:7585962
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:7585962
  review:
    summary: >-
      IDA annotation from Hohfeld et al. (1995), who showed Hip forms
      homo-oligomers. Consistent with the IPI annotations for the same term.
    action: ACCEPT
    reason: >-
      The original Hip paper demonstrated self-association as part of its
      characterization. This provides additional evidence for identical
      protein binding.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:7585962
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:7585962
        supporting_text: >-
          One Hip oligomer binds the ATPase domains of at least two Hsc70 molecules
          dependent on activation of the Hsc70 ATPase by Hsp40.
- term:
    id: GO:1903334
    label: positive regulation of protein folding
  evidence_type: IDA
  original_reference_id: PMID:7585962
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
      - reference_id: PMID:7585962
        supporting_text: >-
          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.
      - reference_id: file:rat/St13/St13-deep-research-falcon.md
        supporting_text: |-
          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
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IDA
  original_reference_id: PMID:7585962
  review:
    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.
    action: ACCEPT
    reason: >-
      The original characterization demonstrated domain-specific binding
      of Hip to the Hsc70 ATPase domain.
- term:
    id: GO:0030544
    label: Hsp70 protein binding
  evidence_type: IDA
  original_reference_id: PMID:7585962
  review:
    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.
    action: ACCEPT
    reason: >-
      The definitive experimental demonstration of Hip binding to Hsc70,
      the core molecular function of this co-chaperone.
    supported_by:
      - reference_id: PMID:7585962
        supporting_text: >-
          One Hip oligomer binds the ATPase domains of at least two Hsc70 molecules
          dependent on activation of the Hsc70 ATPase by Hsp40.
core_functions:
- description: >-
    Hip/St13 functions as a co-chaperone that stabilizes the ADP-bound state of
    Hsc70, promoting substrate retention and enhancing the productive protein
    folding cycle. It binds the ATPase domain of Hsc70 via its TPR domain,
    attenuating the Hsp70 ATPase cycle and competing with nucleotide exchange
    factors.
  molecular_function:
    id: GO:0030544
    label: Hsp70 protein binding
  directly_involved_in:
    - id: GO:0006457
      label: protein folding
    - id: GO:1903334
      label: positive regulation of protein folding
  locations:
    - id: GO:0005829
      label: cytosol
references:
- id: file:rat/St13/St13-deep-research-falcon.md
  title: 'Falcon (Edison Scientific) deep research: Functional Annotation of St13 (Hip/ST13)
    in Rat (UniProt P50503)'
  findings:
    - statement: |-
        Hip/ST13 is a co-chaperone that acts via protein-protein interaction and does not catalyze a chemical reaction, supporting a non-catalytic, Hsp70-binding core molecular function.
      supporting_text: |-
        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.
      reference_section_type: OTHER
    - statement: |-
        Hip binds the Hsp70 nucleotide-binding domain preferentially in the ADP-bound state, stabilizing the high substrate-affinity conformation and delaying client release.
      supporting_text: |-
        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**.
      reference_section_type: OTHER
    - statement: |-
        Hip binds the Hsp70 NBD through a central TPR domain, consistent with the domain-specific binding annotations.
      supporting_text: |-
        A **central TPR domain** that mediates Hsp70 NBD binding
      reference_section_type: OTHER
    - statement: |-
        Rat Hip TPR region forms a structural bracket over the Hsp70 NBD, locking it in the ADP state and delaying substrate release.
      supporting_text: |-
        A rat Hip TPR-containing region forms a **structural “bracket” over the Hsp70 NBD**, obstructing NBD dynamics and thereby **locking Hsp70 in an ADP-bound state and delaying substrate release**.
      reference_section_type: OTHER
    - statement: |-
        Hip stabilizes the ADP-bound conformation, increasing Hsp70 dwell time on substrates and supporting folding, counterbalancing nucleotide exchange factors.
      supporting_text: |-
        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
      reference_section_type: OTHER
    - statement: |-
        Hip and nucleotide exchange factors bind Hsp70 mutually exclusively; Hip competes with BAG1 and other NEFs.
      supporting_text: |-
        Hip binding and NEF binding are **mutually exclusive**
      reference_section_type: OTHER
    - statement: |-
        Hip/ST13 is a cytosolic co-chaperone acting in the cytosolic Hsp70 cycle.
      supporting_text: |-
        Hip/ST13 is described as a **cytosolic** co-chaperone in reviews and mechanistic summaries, consistent with its role in the cytosolic Hsp70 cycle
      reference_section_type: OTHER
    - statement: |-
        Hip has an N-terminal dimerization region involved in homo-oligomerization and forms a dimer in solution.
      supporting_text: |-
        An **N-terminal dimerization region** involved in homo-oligomerization
      reference_section_type: OTHER
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000121
  title: RGD ISO annotations to rat from other mammalian species
  findings: []
- id: PMID:21808025
  title: C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal
    estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection.
  findings: []
- id: PMID:23812373
  title: Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle.
  findings: []
- id: PMID:7585962
  title: Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction
    cycle.
  findings: []
- id: PMID:8999928
  title: Characterization of functional domains of the eukaryotic co-chaperone Hip.
  findings: []
- id: PMID:9183013
  title: Characterization of the molecular-chaperone function of the heat-shock-cognate-70-interacting
    protein.
  findings: []
- id: PMID:9528774
  title: The carboxy-terminal domain of Hsc70 provides binding sites for a distinct
    set of chaperone cofactors.
  findings: []

St13

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

Research Report: Functional Annotation of St13 (Hip/ST13) in Rat (Rattus norvegicus) — UniProt P50503

Executive summary

1) Key concepts and definitions (current understanding)

1.1. What ST13/Hip is

1.2. Position in the Hsp70 cycle

1.3. Domain architecture

2) Primary molecular function and mechanism (rat-relevant mechanistic evidence)

2.1. Structural mechanism (“bracket” model) — rat Hip evidence

2.2. Quantitative binding / state selectivity

2.3. Competition with nucleotide exchange factors (NEFs)

3) Biological processes, pathways, and cellular localization

3.1. Pathway context: cytosolic proteostasis / protein quality control

3.2. Localization

4) Interaction partners and functional network placement

5) Disease-relevant functional evidence (ortholog-informed; not rat-specific)

5.1. Proteostasis in neurodegeneration models

5.2. Cancer-related discussion (older, context-dependent)

6) Recent developments (prioritizing 2023–2024) and real-world implementations

6.1. 2024: Bioprocessing analytics — AAV vector purification residual host cell proteins

6.2. 2023: Human developmental regulatory genomics mention

7) Key statistics and data points (from retrieved studies)

8) Expert interpretation and synthesis (authoritative analysis)

Evidence summary table

Limitations and evidence gaps (important for correct annotation)

Key references (with publication dates and URLs)

Artifacts

Citations

📚 Additional Documentation

Bioreason Rl Predictions

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Bioreason Rl Review

BioReason-Pro RL Review: St13 (rat)

Functional Summary Review

Notes on thinking trace

📄 View Raw YAML