HSPB7 (heat shock protein beta-7), also known as cardiovascular heat shock protein (cvHsp), is a member of the small heat shock protein (sHSP / HSP20, alpha-crystallin domain) family. It is selectively and highly expressed in cardiovascular and insulin-sensitive tissues, predominantly heart and skeletal muscle. HSPB7 binds the actin-crosslinking protein filamin (alpha-filamin / actin-binding protein 280) through its core alpha-crystallin domain and forms hetero-oligomeric complexes with other small heat shock proteins including HSPB8 (HSP22), HSPB2 (MKBP) and HSPB1 (HSP27). Unlike the canonical small HSPs HSPB1 and HSPB5, HSPB7 does not promote refolding of denatured substrates. Instead, it has direct, substrate-selective antiaggregation activity toward polyglutamine-containing proteins. Its N-terminal domain binds early aggregation intermediates and delays their aggregate growth, in a cellular mechanism that depends on autophagy. HSPB7 localizes to the cytoplasm and nucleus and constitutively resides in SC35 nuclear splicing speckles via its N-terminal region. It is implicated in cardiac biology and cardiomyopathy risk.
Definition: Binding to an unfolded or misfolded protein to prevent its aggregation without actively catalyzing refolding. The holdase maintains the client protein in a soluble, folding-competent state.
Justification: HSPB7 directly binds early polyQ/profibrillar intermediates and recombinant HSPB7 delays polyQ aggregation, while it does not improve refolding. This is an in-situ holdase activity not represented by GO:0044183, which requires assisting folding, or GO:0140309, whose definition requires carrier-mediated escort to an acceptor or location. A general term was discussed but not created in go-ontology#30552. GO:0051787 misfolded protein binding is live but, like the obsolete GO:0051082, records client binding only and not the suppression of aggregation. The proposed parent is the molecular_function root because GO has no general chaperone-activity grouping term; GO:0044183 protein folding chaperone is itself a direct child of GO:0003674.
Parent term: molecular_function
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization inferred phylogenetically; HSPB7 is directly documented in the nucleus and constitutively resides in SC35 nuclear splicing speckles. Reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326) and the UniProt subcellular-location record. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002930548 · PANTHER:PTN002930548 SUPPORTS TRANSFER PAINT places nucleus at this ancestral node in PTHR46907 using human HSPB7 (Q9UBY9) as descendant experimental evidence. The target occurring in its own WITH/FROM is valid experimental grounding, not circularity. Supporting Evidence: file:human/HSPB7/HSPB7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19464326}. Nucleus |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic localization inferred phylogenetically; HSPB7 has a documented cytoplasmic pool in addition to its nuclear-speckle residence. Reason: Corroborated by direct experimental (IDA) evidence (PMID:19464326) and the UniProt subcellular-location record. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002930548 · PANTHER:PTN002930548 SUPPORTS TRANSFER PAINT places cytoplasm at this ancestral node in PTHR46907 using human HSPB7 (Q9UBY9) as descendant experimental evidence. The target occurring in its own WITH/FROM is valid experimental grounding, not circularity. Supporting Evidence: file:human/HSPB7/HSPB7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation of nuclear localization, consistent with the IBA and IDA nucleus annotations. Reason: Agrees with stronger experimental evidence (PMID:19464326) placing HSPB7 in the nucleus. Supporting Evidence: file:human/HSPB7/HSPB7-uniprot.txt Nucleus {ECO:0000269|PubMed:19464326} |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation of cytoplasmic localization, redundant with the IBA and IDA cytoplasm annotations. Reason: Correct compartment, agreeing with stronger experimental evidence. Supporting Evidence: file:human/HSPB7/HSPB7-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0007507 heart development | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic annotation to heart development, reflecting HSPB7's cardiac-enriched expression and family associations. No direct experimental demonstration of a role in heart morphogenesis for human HSPB7. Reason: Plausible given the strong cardiac/cardiovascular expression of cvHsp, but derived from an InterPro-to-GO family rule rather than direct experimental evidence for this gene; retained as a non-core process. Supporting Evidence: PMID:10593960 selectively expressed in cardiovascular and insulin-sensitive tissues |
| GO:0015030 Cajal body | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt-SubCell-derived electronic localization to Cajal bodies, consistent with HSPB7's reported sub-nuclear localization to splicing-related nuclear bodies. Reason: Supported by the UniProt subcellular-location record (Cajal body), but sub-nuclear body localization is peripheral to HSPB7's core chaperone/sequestrase function. Supporting Evidence: file:human/HSPB7/HSPB7-uniprot.txt Nucleus, Cajal body {ECO:0000269|PubMed:19464326} |
| GO:0005515 protein binding | IPI PMID:14594798 Interaction of human HSP22 (HSPB8) with other small heat sho... | MODIFY | Summary: Demonstrates that HSPB7 (cvHSP) hetero-dimerizes with the small heat shock protein HSPB8 (HSP22) through a C-C interaction. The bare protein binding term is uninformative; the interaction is with a heat shock protein. Reason: Per curation guidelines, bare protein binding (GO:0005515) is uninformative. The documented partner here is the small HSP HSPB8, so the more informative MF is heat shock protein binding (GO:0031072). Proposed replacements: heat shock protein binding Supporting Evidence: PMID:14594798 HSP22 interacts with itself, cvHSP (HSPB7), MKBP (HSPB2) and HSP27 |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MODIFY | Summary: Proteome-scale interactome screen capturing an HSPB7-HSPB8 (Q9UJY1) interaction. The bare protein binding term is uninformative; the partner is a heat shock protein. Reason: Bare protein binding is uninformative. The WITH partner is HSPB8 (Q9UJY1), a small heat shock protein, so heat shock protein binding (GO:0031072) is the appropriate specific term. Proposed replacements: heat shock protein binding Supporting Evidence: file:human/HSPB7/HSPB7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:16189514 UniProtKB:Q9UJY1 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Yeast two-hybrid human interactome map capturing multiple HSPB7 interactions, including HSPB8 (Q9UJY1) and FLNA (P21333-2), alongside several non-chaperone partners. The bare protein binding term is uninformative. Reason: This collapsed high-throughput signature records genuine interactions, but GO:0005515 is uninformative and its heterogeneous partner set cannot be replaced by one evidence-matched term. Retain the experimentally observed interactions as non-core while representing the specific HSPB8 and filamin interactions separately. Supporting Evidence: file:human/HSPB7/HSPB7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:P21333-2 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: Interactome (BioPlex-type) screen capturing an HSPB7-FLNA (P21333-2) interaction, consistent with HSPB7's documented filamin binding. The bare protein binding term is uninformative. Reason: Bare protein binding is uninformative. The WITH partner is the filamin FLNA (P21333-2), and HSPB7's filamin binding is experimentally established, so filamin binding (GO:0031005) is the appropriate specific molecular function. Proposed replacements: filamin binding Supporting Evidence: file:human/HSPB7/HSPB7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:28514442 UniProtKB:P21333-2 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Reference binary interactome map capturing many HSPB7 interactions, including the co-chaperone BAG3 (O95817), HSPB8 (Q9UJY1) and FLNA (P21333-2). The bare protein binding term is uninformative. Reason: This collapsed high-throughput signature records genuine interactions, but GO:0005515 is uninformative and its heterogeneous partner set cannot be replaced by one evidence-matched term. Retain the experimentally observed interactions as non-core while representing specific HSPB8 and filamin interactions with informative binding terms. Supporting Evidence: file:human/HSPB7/HSPB7-goa.tsv GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:O95817 |
| GO:0015629 actin cytoskeleton | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-ortholog-based electronic localization to the actin cytoskeleton, consistent with HSPB7's binding to the actin-crosslinker filamin. Reason: Plausible given the experimentally established filamin binding, but supported only by ortholog-based electronic inference; retained as a non-core localization. Supporting Evidence: file:human/HSPB7/HSPB7-uniprot.txt Interacts with C-terminal domain of actin-binding protein 280. |
| GO:0031005 filamin binding | IEA GO_REF:0000107 | ACCEPT | Summary: HSPB7 binds alpha-filamin (actin-binding protein 280) through its alpha-crystallin domain; this is a directly documented molecular function of cvHsp, although the GOA annotation here is by ortholog-based electronic inference. Reason: Filamin binding is experimentally established for human cvHsp (PMID:10593960), making this electronic annotation correct and a core molecular function. Supporting Evidence: PMID:10593960 cvHsp interacted in both yeast two-hybrid and immunoprecipitation experiments with alpha-filamin or actin-binding protein 280 file:human/HSPB7/HSPB7-uniprot.txt Interacts with C-terminal domain of actin-binding protein 280. |
| GO:0005634 nucleus | IDA PMID:19464326 HSPB7 is a SC35 speckle resident small heat shock protein. | ACCEPT | Summary: Direct experimental (confocal microscopy) evidence for nuclear localization; HSPB7 constitutively resides in SC35 splicing speckles. Reason: IDA-supported nuclear localization, consistent with UniProt and the SC35-speckle residence. Supporting Evidence: PMID:19464326 HSPB7 constitutively localized to SC35 splicing speckles |
| GO:0005737 cytoplasm | IDA PMID:19464326 HSPB7 is a SC35 speckle resident small heat shock protein. | ACCEPT | Summary: Direct experimental (confocal microscopy) evidence for a cytoplasmic pool of HSPB7. Reason: IDA-supported cytoplasmic localization from the HSPB-family subcellular-distribution survey. Supporting Evidence: file:human/HSPB7/HSPB7-uniprot.txt Cytoplasm {ECO:0000269|PubMed:19464326} |
| GO:0006986 response to unfolded protein | TAS PMID:10593960 Identification and characterization of cvHsp. A novel human ... | KEEP AS NON CORE | Summary: HSPB7 (cvHsp) was described as a small stress protein, but the cached abstract does not report an unfolded-protein challenge or demonstrate that HSPB7 participates in this process. Reason: The TAS annotation is plausible at the small-HSP family level, but PMID:10593960 establishes identity, expression and filamin binding rather than a direct response-to-unfolded-protein stimulus assay. The direct substrate-binding and antiaggregation results in PMID:20843828 and PMID:31097540 establish a molecular activity, not a cellular response initiated by unfolded-protein stimulus. Retain as non-core without elevating it to an experimentally established core process. Supporting Evidence: PMID:10593960 a novel small stress protein of 170 amino acids that we named cvHsp |
| GO:0008016 regulation of heart contraction | TAS PMID:10593960 Identification and characterization of cvHsp. A novel human ... | KEEP AS NON CORE | Summary: Annotation derived from the original cvHsp characterization, reflecting its high cardiac expression and filamin interaction. A direct role in regulating heart contraction is inferred rather than demonstrated. Reason: Plausible given cardiac-restricted expression and filamin (cytoskeletal) binding, but the contractile-regulation role is indirect/inferential; retained as non-core. Supporting Evidence: PMID:10593960 selectively expressed in cardiovascular and insulin-sensitive tissues |
Loading supporting content…
Download this section (compressed HTML)Q: What sequence or conformational features make an aggregation-prone client susceptible to the substrate-selective holdase activity of HSPB7?
Q: Does HSPB7's residence in SC35 splicing speckles reflect a role in RNA/splicing biology, or is it a storage/sequestration site distinct from its cytoskeletal function?
Q: How do HSPB7 hetero-oligomers with HSPB8/BAG3 contribute to chaperone-assisted selective autophagy in cardiomyocytes?
Experiment: Comparative in vitro aggregation assays across polyQ, non-polyQ amyloidogenic, and heat-denatured substrates to define the client scope and kinetic step targeted by HSPB7 holdase activity.
Experiment: Domain-swap and point-mutation analysis of the HSPB7 N-terminal region (1-71) to dissect SC35-speckle targeting versus client sequestration.
Experiment: Cardiomyocyte HSPB7 knockout/knock-in models to test effects on filamin handling, proteostasis, and contractile function.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)