id: P48723
gene_symbol: HSPA13
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: HSPA13 (heat shock 70 kDa protein 13, also called STCH, "stress-70 protein chaperone microsome-associated") is an atypical, non-canonical member of the HSP70 family. It contains an N-terminal signal/leader sequence and the HSP70 nucleotide-binding (ATPase) domain, but it carries a ~50-residue insertion within the ATP-binding domain and truncates the C-terminal substrate (peptide)-binding region characteristic of canonical HSP70 chaperones. Accordingly its ATPase activity is peptide-independent (not stimulated by substrate, unlike BiP or DnaK), and it is not expected to act as a classical substrate-refolding foldase. HSPA13 is a microsome/endoplasmic-reticulum-associated protein that is constitutively expressed in all tissues and induced by calcium ionophore rather than by heat shock. It binds ubiquitin-like (UbL-domain) shuttle proteins including ubiquilins (UBQLN1/2/4) through a short peptide in its ATPase domain, and the SGT co-chaperones SGTA/SGTB, implicating it in protein quality control linked to the ubiquitin-proteasome system rather than in autonomous protein folding.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Nuclear localization inferred phylogenetically from the broad HSP70 PANTHER family. This conflicts with the documented microsomal/ER localization of STCH, which carries an N-terminal signal sequence.
    action: MARK_AS_OVER_ANNOTATED
    reason: The IBA nucleus annotation is transferred from cytosolic/nuclear canonical HSP70s; STCH is a signal-sequence-bearing ER/microsomal protein, so a nuclear site of action is not supported for this paralog.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome. Endoplasmic reticulum.'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Plasma membrane localization inferred phylogenetically from the HSP70 family. Not supported by direct evidence for STCH, which is microsomal/ER-associated.
    action: MARK_AS_OVER_ANNOTATED
    reason: Family-transferred IBA localization that conflicts with the documented ER/microsomal localization of STCH; not supported for this paralog.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome. Endoplasmic reticulum.'
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: STCH retains the HSP70 ATPase domain and has documented ATPase activity (peptide-independent). ATP hydrolysis is a genuine, core molecular function.
    action: ACCEPT
    reason: Directly supported by the original characterization showing STCH ATPase activity, consistent with phylogenetic inference from the HSP70 family.
    supported_by:
    - reference_id: PMID:8131751
      supporting_text: STCH demonstrates ATPase activity that is independent of peptide stimulation
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Inferred HSP70-family heat shock protein binding. Plausible but not directly demonstrated for STCH; its documented partners are ubiquilins and SGT co-chaperones rather than other HSPs.
    action: KEEP_AS_NON_CORE
    reason: Phylogenetic inference of HSP-family interaction; weakly supported for this atypical paralog and not its principal characterized interaction (which is with UbL/ubiquilin shuttle factors).
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-uniprot.txt
      supporting_text: Belongs to the heat shock protein 70 family.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Inferred general protein-folding-chaperone activity transferred from the HSP70 family. STCH truncates the C-terminal peptide-binding domain and has peptide-independent ATPase, so autonomous client-binding chaperone activity is questionable for this paralog.
    action: MARK_AS_OVER_ANNOTATED
    reason: STCH lacks the canonical substrate-binding domain and shows peptide-independent ATPase, making classical chaperone (client-holding/folding) activity unsupported; this is a family-transfer over-annotation.
    supported_by:
    - reference_id: PMID:8131751
      supporting_text: truncates the carboxyl terminal peptide-binding region
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Cytosolic localization inferred phylogenetically from canonical HSP70s. STCH is a signal-sequence-bearing microsomal/ER protein, so a cytosolic site of action is not well supported.
    action: MARK_AS_OVER_ANNOTATED
    reason: Family-transferred IBA localization conflicting with the documented ER/microsomal localization; not supported for this paralog.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome. Endoplasmic reticulum.'
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Inferred protein-refolding process transferred from canonical HSP70 foldases. STCH lacks the substrate-binding domain and has peptide-independent ATPase, so it is not expected to refold clients.
    action: MARK_AS_OVER_ANNOTATED
    reason: Classical HSP70 refolding (foldase) activity is not supported for STCH, which truncates the peptide-binding region; this is a family-transfer over-annotation.
    supported_by:
    - reference_id: PMID:8131751
      supporting_text: truncates the carboxyl terminal peptide-binding region
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: STCH contains the HSP70 nucleotide-binding domain and binds ATP. ATP binding is a core molecular function underlying its ATPase activity.
    action: ACCEPT
    reason: Directly supported by the conserved HSP70 ATPase domain and documented ATPase activity.
    supported_by:
    - reference_id: PMID:8131751
      supporting_text: STCH demonstrates ATPase activity that is independent of peptide stimulation
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Endoplasmic reticulum / microsomal localization, the documented compartment for STCH, which carries an N-terminal signal sequence and is enriched in microsomes.
    action: ACCEPT
    reason: Directly supported by the original characterization showing microsome enrichment and by the UniProt subcellular-location record.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Microsome. Endoplasmic reticulum.'
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic annotation of ATP hydrolysis activity, redundant with the IBA annotation and supported by direct evidence.
    action: ACCEPT
    reason: Consistent with the documented peptide-independent ATPase activity of STCH.
    supported_by:
    - reference_id: PMID:8131751
      supporting_text: STCH demonstrates ATPase activity that is independent of peptide stimulation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Proteome-scale interactome screen capturing an STCH-UBQLN1 (Q9UMX0) interaction. The bare protein binding term is uninformative; the partner is a ubiquilin, consistent with the documented UbL-protein interaction.
    action: KEEP_AS_NON_CORE
    reason: Records a genuine interaction with the ubiquilin UBQLN1 (reflecting STCH's characterized binding of UbL shuttle factors), but the bare term is uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16189514 UniProtKB:Q9UMX0
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  qualifier: enables
  review:
    summary: Inherited-ataxia interactome network capturing an STCH-UBQLN4 (Q9NRR5) interaction. The bare protein binding term is uninformative; the partner is a ubiquilin.
    action: KEEP_AS_NON_CORE
    reason: Records a genuine ubiquilin (UBQLN4) interaction consistent with STCH's UbL-binding function, but the bare term is uninformative.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16713569 UniProtKB:Q9NRR5
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: Human liver interactome screen capturing an STCH-UBQLN1 (Q9UMX0) interaction. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a genuine ubiquilin interaction but the bare term is uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:21988832 UniProtKB:Q9UMX0
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Yeast two-hybrid interactome map capturing STCH interactions with SGTA (O43765) and UBQLN1 (Q9UMX0). The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records genuine interactions with an SGT co-chaperone and a ubiquilin, consistent with STCH's quality-control role, but the bare term is uninformative.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:O43765
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Human interactome (protein communities) study capturing an STCH-B4GALT5 (O43286) interaction. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; records a genuine interaction but uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:O43286
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Reference binary interactome map capturing multiple STCH interactions, including SGTA, SGTB, CRYGA and the ubiquilins UBQLN1/UBQLN2. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records genuine interactions with co-chaperones (SGTA/SGTB) and ubiquilins, consistent with STCH's quality-control associations, but the bare term is uninformative.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:Q9UHD9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing an STCH-B4GALT5 (O43286) interaction. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome data; records a genuine interaction but uninformative as a molecular function.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:O43286
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35914814
  qualifier: enables
  review:
    summary: Chromosome-21 protein-protein interaction study capturing STCH interactions with SGTB and the ubiquilins UBQLN1/UBQLN2/UBQLN4. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records genuine interactions with an SGT co-chaperone and ubiquilins, consistent with STCH's UbL-binding quality-control role, but the bare term is uninformative.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:35914814 UniProtKB:Q9NRR5
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of STCH in extracellular exosomes. A peripheral localization, not the principal site of STCH function.
    action: KEEP_AS_NON_CORE
    reason: Mass-spectrometry detection in exosomes records a real pool but is peripheral to STCH's ER/microsomal quality-control function.
    supported_by:
    - reference_id: file:human/HSPA13/HSPA13-goa.tsv
      supporting_text: GO:0070062 extracellular exosome cellular_component ECO:0007005 HDA
- term:
    id: GO:0043231
    label: intracellular membrane-bounded organelle
  evidence_type: TAS
  original_reference_id: PMID:8131751
  qualifier: located_in
  review:
    summary: Curated localization to an intracellular membrane-bounded organelle, consistent with STCH's documented microsomal/ER localization, though this term is generic.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the documented ER/microsomal localization but the term is non-specific; the precise compartment is better captured by the endoplasmic reticulum annotation.
    supported_by:
    - reference_id: PMID:8131751
      supporting_text: is enriched in a membrane-bound microsome fraction
references:
- 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 of UniProtKB entries based on the manual curation of subcellular locations
  findings: []
- id: PMID:8131751
  title: Stch encodes the 'ATPase core' of a microsomal stress 70 protein.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_8131751.md title matches; also anchored to GOA (TAS, GO:0043231). The defining characterization of STCH/HSPA13 as a microsomal HSP70 with peptide-independent ATPase activity and a truncated substrate-binding domain; supports core_function GO:0016887. (Gene is poorly characterized overall, but this paper is directly on-target.)"
  findings:
  - statement: STCH/HSPA13 is a microsome-associated HSP70-family member with a hydrophobic leader sequence, a ~50-residue insertion in the ATP-binding domain and a truncated C-terminal peptide-binding region; it has peptide-independent ATPase activity, is constitutively expressed, and is induced by calcium ionophore but not by heat shock.
    reference_section_type: RESULTS
- id: PMID:10675567
  title: A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-like Stch.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_10675567.md title matches and confirms that ubiquitin-like (ubiquilin/BAG6-type) proteins bind a peptide in the STCH ATPase domain; directly supports core_function GO:0032182 (ubiquitin-like protein binding). Not GOA-anchored but the cached content is on-target."
  findings:
  - statement: Ubiquitin-like (UbL) proteins (ubiquilin/Dsk2-type Chap1 and scythe/BAG6-type Chap2) bind a short peptide within the ATPase domain of STCH, linking the HSP70-like ATPase to ubiquitin-proteasome-associated regulation of the cell cycle and apoptosis.
    reference_section_type: RESULTS
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35914814
  title: 'Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer''s disease.'
  findings: []
- id: file:human/HSPA13/HSPA13-uniprot.txt
  title: UniProt entry P48723 (HSP13_HUMAN), Heat shock 70 kDa protein 13 (STCH)
  findings:
  - statement: Atypical microsomal/ER HSP70-family protein with peptide-independent ATPase activity; binds ubiquilins (UBQLN1/2/4) and SGTA/SGTB; constitutively expressed; signal-sequence-bearing.
    reference_section_type: OTHER
core_functions:
- description: Microsomal/endoplasmic-reticulum-associated atypical HSP70-family protein that hydrolyzes ATP in a peptide-independent manner via its conserved nucleotide-binding domain, lacking the canonical substrate-binding domain of foldase HSP70s.
  molecular_function:
    id: GO:0016887
    label: ATP hydrolysis activity
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: PMID:8131751
    supporting_text: STCH demonstrates ATPase activity that is independent of peptide stimulation
  - reference_id: file:human/HSPA13/HSPA13-uniprot.txt
    supporting_text: 'SUBCELLULAR LOCATION: Microsome. Endoplasmic reticulum.'
- description: Binds ubiquitin-like (UbL-domain) shuttle proteins, including ubiquilins (UBQLN1/2/4), through a short peptide in its ATPase domain, and SGT co-chaperones, linking it to ubiquitin-proteasome-associated protein quality control rather than autonomous protein folding.
  molecular_function:
    id: GO:0032182
    label: ubiquitin-like protein binding
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  supported_by:
  - reference_id: PMID:10675567
    supporting_text: two human ubiquitin-like (UbL) proteins that bind to a short peptide within the ATPase domain of the Hsp70-like Stch protein
proposed_new_terms: []
suggested_questions:
- question: Given its truncated peptide-binding domain and peptide-independent ATPase, does HSPA13/STCH retain any substrate-binding (holdase) capacity, or does it act purely as an ATPase scaffold?
- question: What is the functional role of the STCH-ubiquilin (UbL) interaction in ER-associated degradation or ribosome/translocon quality control?
- question: Why is STCH induced by calcium stress but not heat shock, and what transcriptional program controls it?
suggested_experiments:
- description: Biochemical reconstitution to test whether recombinant STCH can bind/hold model unfolded substrates, and whether its ATPase is modulated by ubiquilins or SGTA/SGTB.
- description: Proximity labeling and topology analysis to define the precise ER/microsomal membrane association and orientation of STCH and its interaction partners.
- description: Loss-of-function (knockout/knockdown) studies assessing effects on ER-associated degradation, ubiquilin-dependent proteasomal targeting, and the calcium-stress response.