Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) nuclear localization, corroborated by direct experimental evidence that HSPB2 localizes to nuclear foci. Reason: Nuclear localization is directly supported (PMID:19464326, HPA nucleoplasm IDA) in addition to the IBA transfer. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Note=Localizes to nuclear foci.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) cytoplasmic localization, corroborated by direct evidence; HSPB2 is a cytosolic muscle sHSP localizing to the myofibrillar Z-membrane. Reason: Cytoplasmic localization is directly supported (PMID:19464326 IDA; TAS cytosol) and is a principal site of HSPB2 chaperone action. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0043066 negative regulation of apoptotic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic transfer of the cytoprotective/anti-apoptotic role common to small HSPs. Consistent with HSPB2's cardioprotective (anti-ischemic) phenotype, but a downstream consequence of its chaperone activity rather than a direct molecular function. Reason: A plausible downstream cytoprotective effect supported by the cardioprotection phenotype, but secondary to HSPB2's core holdase/kinase-activator functions. Supporting Evidence: PMID:26465331 transgenic overexpressing mice including reduced infarct size and maintenance of
GO:0009408 response to heat	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic transfer of "response to heat" from the heat-shock protein family. Notably HSPB2/MKBP is NOT induced by heat shock, though it participates in the muscle stress response and protects clients from heat-induced damage. Reason: HSPB2 expression is not heat-inducible, so the term applies only loosely via its stress-protective chaperone activity; retained as non-core. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt The expression of MKBP is not induced by heat shock
GO:0042026 protein refolding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA transfer of "protein refolding". Small HSPs are ATP-independent holdases that bind and sequester non-native proteins; they do not autonomously refold clients, which requires downstream ATP-dependent chaperones (HSP70/HSP100). Reason: Mechanistically HSPB2 is a holdase, not a foldase; refolding is a downstream outcome of the wider chaperone system, so this is non-core. The holdase activity is better captured by unfolded protein binding. Supporting Evidence: PMID:26465331 validated as a potential client protein of HspB2 through chaperone assays
GO:0005212 structural constituent of eye lens	IEA GO_REF:0000002	REMOVE	Summary: InterPro2GO transfer of the lens structural role from the alpha-crystallin domain signature. HSPB2 is explicitly not expressed in the lens, so this is an erroneous family-level over-annotation. Reason: HSPB2 is not a lens crystallin and is expressly absent from the lens; the term is incorrectly transferred from the broader alpha-crystallin/sHSP family. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Expressed preferentially in skeletal muscle and heart but not in the lens.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (UniProt SubCell) nuclear localization, redundant with the experimental IDA nuclear annotation. Reason: Correct, supported by direct experimental evidence for nuclear foci. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Note=Localizes to nuclear foci.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (UniProt SubCell) cytoplasmic localization, redundant with the experimental IDA cytoplasm annotation. Reason: Correct, supported by direct experimental evidence. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0005515 protein binding	IPI PMID:14594798 Interaction of human HSP22 (HSPB8) with other small heat sho...	MODIFY	Summary: Interaction with the small heat-shock protein HSPB8/HSP22 (Q9UJY1). This sHSP-sHSP interaction is more informatively captured as heat shock protein binding than bare protein binding. Reason: The partner is another heat-shock protein (HSPB8), so heat shock protein binding is the appropriate specific molecular function. Proposed replacements: heat shock protein binding Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Q16082; Q9UJY1: HSPB8; NbExp=3; IntAct=EBI-739395, EBI-739074
GO:0005515 protein binding	IPI PMID:23188086 Binding determinants of the small heat shock protein, αB-cry...	MODIFY	Summary: Interaction with the small heat-shock protein alphaB-crystallin/CRYAB (P02511), reflecting sHSP hetero-oligomer recognition via the IxI motif. Reason: The partner is another heat-shock protein (CRYAB), so heat shock protein binding is the appropriate specific molecular function. Proposed replacements: heat shock protein binding Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Q16082; P02511: CRYAB; NbExp=3; IntAct=EBI-739395, EBI-739060
GO:0005515 protein binding	IPI PMID:26465331 Characterization of the Cardiac Overexpression of HSPB2 Reve...	MODIFY	Summary: Cardiac yeast two-hybrid interactome again capturing the HSPB2-CRYAB interaction (and broader myofibrillar/mitochondrial clients). The sHSP-sHSP interaction is better captured as heat shock protein binding. Reason: Partner is the heat-shock protein CRYAB; heat shock protein binding is the specific molecular function. The wider client-binding role is captured by unfolded protein binding in core functions. Proposed replacements: heat shock protein binding Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Q16082; P02511: CRYAB; NbExp=3; IntAct=EBI-739395, EBI-739060
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Large binary HuRI interactome screen capturing many heterogeneous partners (BAG3, A1CF, CEP19, POGZ, VEZF1 and others). Bare protein binding is uninformative. Reason: High-throughput binary interactions; bare protein binding is not elevated to core and the partners are mostly unrelated to HSPB2's chaperone function. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Q16082; O95817: BAG3; NbExp=5; IntAct=EBI-739395, EBI-747185
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Neurodegeneration interactome screen capturing an HSPB2-APP (amyloid precursor protein) interaction. Bare protein binding from a single high-throughput screen. Reason: An isolated high-throughput interaction; uninformative bare protein binding, not part of the core muscle/chaperone function. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Q16082; P05067: APP; NbExp=3; IntAct=EBI-739395, EBI-77613
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex affinity-purification interactome capturing an HSPB2-BAG3 interaction. BAG3 is a co-chaperone that cooperates with small HSPs; nonetheless this is a bare protein binding annotation. Reason: Records a real interaction with the sHSP co-chaperone BAG3 but as an uninformative bare-binding annotation; retained as non-core. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Q16082; O95817: BAG3; NbExp=5; IntAct=EBI-739395, EBI-747185
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence localization to the nucleoplasm, consistent with the reported nuclear foci. Reason: Direct antibody-based localization consistent with the documented nuclear pool. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Note=Localizes to nuclear foci.
GO:0005515 protein binding	IPI PMID:25556234 New host factors important for respiratory syncytial virus (...	KEEP AS NON CORE	Summary: AgBase-curated interaction (with P0DOE7) reported in a respiratory syncytial virus host-factor screen. Bare protein binding, unrelated to HSPB2's core function. Reason: Isolated screen-derived interaction; uninformative bare protein binding. Supporting Evidence: file:human/HSPB2/HSPB2-goa.tsv UniProtKB:P0DOE7
GO:0005634 nucleus	IDA PMID:19464326 HSPB7 is a SC35 speckle resident small heat shock protein.	ACCEPT	Summary: Direct experimental demonstration that HSPB2 localizes to the nucleus (nuclear foci). Reason: Strongest-evidence nuclear localization. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Note=Localizes to nuclear foci.
GO:0005737 cytoplasm	IDA PMID:19464326 HSPB7 is a SC35 speckle resident small heat shock protein.	ACCEPT	Summary: Direct experimental demonstration that HSPB2 localizes to the cytoplasm. Reason: Strongest-evidence cytoplasmic localization; principal site of HSPB2 action. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0006986 response to unfolded protein	NAS PMID:9344664 Identification and characterization of the gene encoding a n...	KEEP AS NON CORE	Summary: HSPB2 is an alpha-crystallin/small-HSP family member implicated in the stress response to unfolded proteins. Consistent with its holdase chaperone activity. Reason: A reasonable stress-response process annotation; the underlying molecular activity (binding non-native proteins) is the core feature captured by unfolded protein binding. Supporting Evidence: file:human/HSPB2/HSPB2-uniprot.txt Belongs to the small heat shock protein (HSP20) family.
GO:0005829 cytosol	TAS PMID:9490724 MKBP, a novel member of the small heat shock protein family,...	ACCEPT	Summary: Author-stated cytosolic localization; in muscle cytosol HSPB2/MKBP exists as an oligomeric complex distinct from the CRYAB/HSP27 complex. Reason: Supported by the original MKBP characterization; cytosol is a principal site of HSPB2 oligomers. Supporting Evidence: PMID:9490724 MKBP exists as an oligomeric complex separate from the complex
GO:0008047 enzyme activator activity	TAS PMID:9490724 MKBP, a novel member of the small heat shock protein family,...	ACCEPT	Summary: HSPB2/MKBP binds the myotonic dystrophy protein kinase (DMPK), enhances its kinase activity and protects it from heat-induced inactivation, acting as a kinase activator. This is a distinctive, well-documented HSPB2 function. Reason: Directly demonstrated in vitro; HSPB2 enhances DMPK kinase activity, a genuine and specific enzyme-activator (kinase-activator) function. Supporting Evidence: PMID:9490724 enhances the kinase activity of DMPK and protects it from heat-induced

Core Functions

ATP-independent small heat-shock protein (holdase) that binds non-native/destabilized client proteins via its alpha-crystallin domain to prevent their aggregation under stress, holding them for downstream refolding (validated client GAPDH).

Molecular Function:

unfolded protein binding

Cellular Locations:

cytoplasm nucleus

Supporting Evidence:

PMID:26465331
validated as a potential client protein of HspB2 through chaperone assays
file:human/HSPB2/HSPB2-uniprot.txt
Belongs to the small heat shock protein (HSP20) family.

DMPK kinase activator; HSPB2/MKBP binds the myotonic dystrophy protein kinase, enhances its kinase activity and protects it from heat-induced inactivation, constituting a muscle stress-responsive system.

Molecular Function:

enzyme activator activity

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:9490724
enhances the kinase activity of DMPK and protects it from heat-induced

References

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 conservation of the subcellular location

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:9344664

Identification and characterization of the gene encoding a new member of the alpha-crystallin/small hsp family, closely linked to the alphaB-crystallin gene in a head-to-head manner.

PMID:9490724

MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase.

HSPB2/MKBP is a small HSP that binds DMPK, enhances its kinase activity and protects it from heat-induced inactivation; it forms an oligomeric muscle-cytosol complex distinct from the alphaB-crystallin/HSP27 complex and is not induced by heat shock.

PMID:14594798

Interaction of human HSP22 (HSPB8) with other small heat shock proteins.

PMID:19464326

HSPB7 is a SC35 speckle resident small heat shock protein.

HSPB2 localizes to both the cytoplasm and the nucleus (nuclear foci).

PMID:23188086

Binding determinants of the small heat shock protein, αB-crystallin: recognition of the 'IxI' motif.

PMID:25556234

New host factors important for respiratory syncytial virus (RSV) replication revealed by a novel microfluidics screen for interactors of matrix (M) protein.

PMID:26465331

Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome.

Cardiac HSPB2 overexpression is cardioprotective in ischemia (reduced infarct, maintained ATP); HSPB2 has a myofibrillar/mitochondrial cardiac interactome and GAPDH was validated as a client protein via chaperone assays.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

file:human/HSPB2/HSPB2-uniprot.txt

UniProt entry Q16082 (HSPB2_HUMAN), Heat shock protein beta-2 (MKBP)

Small heat-shock protein (HSP20/alpha-crystallin family) expressed in skeletal muscle and heart but not lens; binds and may activate DMPK; localizes to cytoplasm and nucleus (nuclear foci).

Suggested Experiments

Experiment: In vitro aggregation-protection (holdase) assays with recombinant HSPB2 against model and physiological clients (e.g. GAPDH) to quantify chaperone activity and ATP-independence.

Experiment: Reconstitute DMPK with HSPB2 to map the binding interface and measure kinase-activation kinetics, testing whether disease-associated changes alter activation.

Experiment: Define the muscle HSPB2/HSPB3 complex stoichiometry by size-exclusion/native MS and test client specificity relative to HSPB2 alone.

📚 Additional Documentation

Notes

(HSPB2-notes.md)

HSPB2 (HspB2 / MKBP) research notes

Identity

UniProt Q16082 (HSPB2_HUMAN), 182 aa. HGNC:5247. AltName: DMPK-binding protein (MKBP). Small heat-shock protein (HSP20/alpha-crystallin) family; sHSP/ACD domain 55-163.
Gene head-to-head with CRYAB (alphaB-crystallin) on chr11. Expressed preferentially in skeletal muscle and heart (not lens).

Function

ATP-independent small HSP (holdase-type chaperone). Identified as MKBP, binds and activates myotonic dystrophy protein kinase (DMPK) and protects it from heat-induced inactivation.
PMID:9490724
[UniProt FUNCTION "May regulate the kinase DMPK." SUBUNIT "Interacts with DMPK; may enhance its kinase activity."]
Forms its own oligomeric complex in muscle cytosol, separate from the alphaB-crystallin/HSP27 complex; not heat-inducible but redistributes to insoluble fraction under stress.
[PMID:9490724 "In muscle cytosol, MKBP exists as an oligomeric complex separate from the complex formed by alphaB-crystallin and HSP27." / "The expression of MKBP is not induced by heat shock"]
Localizes to the Z-membrane of myofibrils and the neuromuscular junction (where DMPK concentrates).
Cardiac overexpression is cardioprotective in ischemia (reduced infarct size, maintained ATP); has a mitochondrial-leaning "cardiac interactome"; validated client GAPDH via chaperone assays.
[PMID:26465331 "exhibited ischemic cardioprotection in transgenic overexpressing mice including reduced infarct size and maintenance of ATP levels" / "validated as a potential client protein of HspB2 through chaperone assays"]

Localization

Cytoplasm and nucleus (nuclear foci) (IDA, PMID:19464326). HPA nucleoplasm IDA. TAS cytosol (PMID:9490724).

Interactions

DMPK (functional, PMID:9490724). CRYAB/alphaB-crystallin (P02511; PMID:23188086, 26465331) — sHSP hetero-association. HSPB8/HSP22 (Q9UJY1; PMID:14594798) — sHSP interaction. BAG3 (O95817; PMID:32296183/33961781) — co-chaperone of sHSP/autophagy. APP (P05067; PMID:32814053). Many HuRI binary hits (PMID:32296183) — mostly uninformative.
Orchestrator note mentions HSPB3 partner; HSPB2-HSPB3 form a known sHSP complex in muscle (literature), though HSPB3 is not among the cached GOA partners here.

GO annotation review reasoning

unfolded protein binding (IBA, GO:0051082) — ACCEPT; core sHSP holdase MF (binds non-native proteins to prevent aggregation). Confirmed by GAPDH client chaperone assay.
enzyme activator activity (TAS, GO:0008047, PMID:9490724) — ACCEPT/core; specifically enhances DMPK kinase activity (kinase activator).
protein refolding (IBA, GO:0042026) — sHSPs are holdases, not foldases; they hold substrates for downstream ATP-dependent refolding by HSP70. KEEP_AS_NON_CORE (mislabels mechanism but reflects downstream outcome).
response to heat (IBA, GO:0009408) — KEEP_AS_NON_CORE; note HSPB2 is NOT heat-inducible, but participates in stress response; family-level term.
response to unfolded protein (NAS, GO:0006986, PMID:9344664) — ACCEPT/KEEP; stress-response role.
negative regulation of apoptotic process (IBA, GO:0043066) — KEEP_AS_NON_CORE; sHSP cytoprotective family role; cardioprotection consistent.
structural constituent of eye lens (IEA InterPro, GO:0005212) — REMOVE/MARK_AS_OVER_ANNOTATED; HSPB2 is explicitly NOT expressed in lens; transferred from alpha-crystallin family.
nucleus / cytoplasm / cytosol / nucleoplasm — ACCEPT (well supported by IDA).
protein binding (IPI) — the CRYAB and HSPB8 sHSP interactions could MODIFY to heat shock protein binding (GO:0031072); BAG3 etc; bare Y2H -> KEEP_AS_NON_CORE.

Core functions

ATP-independent holdase chaperone (unfolded protein binding) — sHSP preventing aggregation of client proteins (e.g. GAPDH).
DMPK kinase activator / enzyme activator activity — binds and activates DMPK, protecting from heat inactivation.

Pn Notes

(HSPB2-pn-notes.md)

HSPB2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q16082
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/HSPB2/HSPB2-ai-review.yaml
AIGR review HTML: present - genes/human/HSPB2/HSPB2-ai-review.html
Gene notes: present - genes/human/HSPB2/HSPB2-notes.md
GOA TSV: present - genes/human/HSPB2/HSPB2-goa.tsv
UniProt record: present - genes/human/HSPB2/HSPB2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/HSPB2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/HSPB2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: HSPB2 (heat shock protein beta-2; also MKBP, "DMPK-binding protein") is an ATP-independent small heat-shock protein (sHSP) of the alpha-crystallin/HSP20 family, expressed preferentially in skeletal and cardiac muscle. Like other sHSPs it acts as a holdase chaperone, binding non-native/destabilized client proteins through its alpha-crystallin domain to prevent their aggregation under stress, holding them for downstream ATP-dependent refolding. HSPB2 forms its own oligomeric complex in muscle cytosol, distinct from the alphaB-crystallin (CRYAB)/HSP27 complex, and is notable for binding and activating the myotonic dystrophy protein kinase (DMPK), enhancing its kinase activity and protecting it from heat-induced inactivation. It localizes to the cytoplasm (Z-membrane of myofibrils and the neuromuscular junction) and to nuclear foci. HSPB2 is not strongly heat-inducible but participates in the muscle stress response and is cardioprotective during ischemia, helping maintain ATP levels.
Existing/core annotation action counts: ACCEPT: 9; KEEP_AS_NON_CORE: 8; MODIFY: 3; REMOVE: 1

PN Consistency Summary

Consistency: Largely consistent. Deep research, notes, and review YAML agree HSPB2 is an ATP-independent small HSP (alpha-crystallin/HSP20) holdase (core MF GO:0051082 unfolded protein binding; validated client GAPDH, PMID:26465331) and a DMPK kinase activator (core MF GO:0008047, PMID:9490724). PN "small HSP" placement matches. The CY+MI dual branch fits HSPB2's cytosolic muscle oligomers plus a cardiac mitochondrial-leaning interactome (PMID:26465331). No contradiction; note review REMOVES GO:0005212 (eye-lens crystallin) as an erroneous family transfer — a good catch the PN small-HSP node does not propagate.
PN story / NEW pressure: PN asserts GO:0044183 protein folding chaperone (verified real). GOA lacks GO:0044183 (new_to_goa correct). GO:0044183 sits on the chaperone-ACTIVITY branch, sibling to the review's GO:0051082 (on the binding branch) — neither is ancestor of the other; both are defensible for a sHSP holdase. GO:0044183 is broader/coarser than the review's holdase-specific framing but not wrong. Reasonable ADD; not over-reaching for a bona fide sHSP.
Evidence alignment: PN rows no titles; review anchors on PMID:9490724 (MKBP/DMPK, TAS) and PMID:26465331 (cardiac interactome/GAPDH client) — both VERIFIED. No conflict.
Verdict: Consistent. GO:0044183 is a defensible new_to_goa ADD (broader sibling of review's GO:0051082, both valid for a sHSP holdase). DMPK-activator and lens-removal are gene-specific calls outside the PN family mapping.

Full Consistency Review

UniProt: Q16082 (MKBP) · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
PN placement: two rows — Cytonuclear proteostasis|Chaperone|small HSP system|small HSP (type=mapped) and Mitochondrial proteostasis|Chaperone|small HSP (group=mapped); PN-node mapping: both → GO:0044183 protein folding chaperone, scope=ok_for_propagation_to_go, projected new_to_goa; class/branch=no_mapping.
Consistency: Largely consistent. Deep research, notes, and review YAML agree HSPB2 is an ATP-independent small HSP (alpha-crystallin/HSP20) holdase (core MF GO:0051082 unfolded protein binding; validated client GAPDH, PMID:26465331) and a DMPK kinase activator (core MF GO:0008047, PMID:9490724). PN "small HSP" placement matches. The CY+MI dual branch fits HSPB2's cytosolic muscle oligomers plus a cardiac mitochondrial-leaning interactome (PMID:26465331). No contradiction; note review REMOVES GO:0005212 (eye-lens crystallin) as an erroneous family transfer — a good catch the PN small-HSP node does not propagate.
PN story / NEW pressure: PN asserts GO:0044183 protein folding chaperone (verified real). GOA lacks GO:0044183 (new_to_goa correct). GO:0044183 sits on the chaperone-ACTIVITY branch, sibling to the review's GO:0051082 (on the binding branch) — neither is ancestor of the other; both are defensible for a sHSP holdase. GO:0044183 is broader/coarser than the review's holdase-specific framing but not wrong. Reasonable ADD; not over-reaching for a bona fide sHSP.
Mapping strategy: Node status unchanged. Projection accurate (term absent from GOA). GO:0044183 is appropriately generic for the "small HSP" type; the review's GO:0051082 + holdase (GO:0140309 territory) is the more precise gene-level call. Minor altitude divergence only.
Evidence alignment: PN rows no titles; review anchors on PMID:9490724 (MKBP/DMPK, TAS) and PMID:26465331 (cardiac interactome/GAPDH client) — both VERIFIED. No conflict.
Verdict: Consistent. GO:0044183 is a defensible new_to_goa ADD (broader sibling of review's GO:0051082, both valid for a sHSP holdase). DMPK-activator and lens-removal are gene-specific calls outside the PN family mapping.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/HSPB2/HSPB2-ai-review.yaml
PN workbook rows: 2

PN row 1: Cytonuclear proteostasis | Chaperone | small HSP system | small HSP

UniProt: Q16082
In branches: CY, MI
PN-node mapping records (path + ancestors):
- [type] Cytonuclear proteostasis|Chaperone|small HSP system|small HSP
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0044183 protein folding chaperone]
  rationale: This PN type denotes small heat-shock chaperones. Protein folding chaperone is the appropriate shared molecular-function term.
- [group] Cytonuclear proteostasis|Chaperone|small HSP system
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower taxonomy bucket that is already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
- [class] Cytonuclear proteostasis|Chaperone
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
- [branch] Cytonuclear proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Mitochondrial proteostasis | Chaperone | small HSP

UniProt: Q16082
In branches: CY, MI
PN-node mapping records (path + ancestors):
- [group] Mitochondrial proteostasis|Chaperone|small HSP
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0044183 protein folding chaperone]
  rationale: This PN group denotes mitochondrial small heat-shock chaperones. Protein folding chaperone is the appropriate shared molecular-function term.
- [class] Mitochondrial proteostasis|Chaperone
  status=no_mapping scope= GO=[]
  rationale: This PN class is too heterogeneous for a single safe GO mapping. In the workbook it mixes HSP70, HSP60, and HSP90 systems, small intermembrane-space chaperones, membrane-protein chaperones, and other mitochondrial-specific factors.
- [branch] Mitochondrial proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (2)

GO:0044183 protein folding chaperone | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Cytonuclear proteostasis|Chaperone|small HSP system|small HSP
GO:0044183 protein folding chaperone | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Mitochondrial proteostasis|Chaperone|small HSP

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q16082
gene_symbol: HSPB2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: HSPB2 (heat shock protein beta-2; also MKBP, "DMPK-binding protein") is an ATP-independent small heat-shock protein (sHSP) of the alpha-crystallin/HSP20 family, expressed preferentially in skeletal and cardiac muscle. Like other sHSPs it acts as a holdase chaperone, binding non-native/destabilized client proteins through its alpha-crystallin domain to prevent their aggregation under stress, holding them for downstream ATP-dependent refolding. HSPB2 forms its own oligomeric complex in muscle cytosol, distinct from the alphaB-crystallin (CRYAB)/HSP27 complex, and is notable for binding and activating the myotonic dystrophy protein kinase (DMPK), enhancing its kinase activity and protecting it from heat-induced inactivation. It localizes to the cytoplasm (Z-membrane of myofibrils and the neuromuscular junction) and to nuclear foci. HSPB2 is not strongly heat-inducible but participates in the muscle stress response and is cardioprotective during ischemia, helping maintain ATP levels.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) nuclear localization, corroborated by direct experimental evidence that HSPB2 localizes to nuclear foci.
    action: ACCEPT
    reason: Nuclear localization is directly supported (PMID:19464326, HPA nucleoplasm IDA) in addition to the IBA transfer.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: Note=Localizes to nuclear foci.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) cytoplasmic localization, corroborated by direct evidence; HSPB2 is a cytosolic muscle sHSP localizing to the myofibrillar Z-membrane.
    action: ACCEPT
    reason: Cytoplasmic localization is directly supported (PMID:19464326 IDA; TAS cytosol) and is a principal site of HSPB2 chaperone action.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic transfer of the cytoprotective/anti-apoptotic role common to small HSPs. Consistent with HSPB2's cardioprotective (anti-ischemic) phenotype, but a downstream consequence of its chaperone activity rather than a direct molecular function.
    action: KEEP_AS_NON_CORE
    reason: A plausible downstream cytoprotective effect supported by the cardioprotection phenotype, but secondary to HSPB2's core holdase/kinase-activator functions.
    supported_by:
    - reference_id: PMID:26465331
      supporting_text: transgenic overexpressing mice including reduced infarct size and maintenance of
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic transfer of "response to heat" from the heat-shock protein family. Notably HSPB2/MKBP is NOT induced by heat shock, though it participates in the muscle stress response and protects clients from heat-induced damage.
    action: KEEP_AS_NON_CORE
    reason: HSPB2 expression is not heat-inducible, so the term applies only loosely via its stress-protective chaperone activity; retained as non-core.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: The expression of MKBP is not induced by heat shock
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IBA transfer of "protein refolding". Small HSPs are ATP-independent holdases that bind and sequester non-native proteins; they do not autonomously refold clients, which requires downstream ATP-dependent chaperones (HSP70/HSP100).
    action: KEEP_AS_NON_CORE
    reason: Mechanistically HSPB2 is a holdase, not a foldase; refolding is a downstream outcome of the wider chaperone system, so this is non-core. The holdase activity is better captured by unfolded protein binding.
    supported_by:
    - reference_id: PMID:26465331
      supporting_text: validated as a potential client protein of HspB2 through chaperone assays
- term:
    id: GO:0005212
    label: structural constituent of eye lens
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO transfer of the lens structural role from the alpha-crystallin domain signature. HSPB2 is explicitly not expressed in the lens, so this is an erroneous family-level over-annotation.
    action: REMOVE
    reason: HSPB2 is not a lens crystallin and is expressly absent from the lens; the term is incorrectly transferred from the broader alpha-crystallin/sHSP family.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: Expressed preferentially in skeletal muscle and heart but not in the lens.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic (UniProt SubCell) nuclear localization, redundant with the experimental IDA nuclear annotation.
    action: ACCEPT
    reason: Correct, supported by direct experimental evidence for nuclear foci.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: Note=Localizes to nuclear foci.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic (UniProt SubCell) cytoplasmic localization, redundant with the experimental IDA cytoplasm annotation.
    action: ACCEPT
    reason: Correct, supported by direct experimental evidence.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14594798
  qualifier: enables
  review:
    summary: Interaction with the small heat-shock protein HSPB8/HSP22 (Q9UJY1). This sHSP-sHSP interaction is more informatively captured as heat shock protein binding than bare protein binding.
    action: MODIFY
    reason: The partner is another heat-shock protein (HSPB8), so heat shock protein binding is the appropriate specific molecular function.
    proposed_replacement_terms:
    - id: GO:0031072
      label: heat shock protein binding
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'Q16082; Q9UJY1: HSPB8; NbExp=3; IntAct=EBI-739395, EBI-739074'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23188086
  qualifier: enables
  review:
    summary: Interaction with the small heat-shock protein alphaB-crystallin/CRYAB (P02511), reflecting sHSP hetero-oligomer recognition via the IxI motif.
    action: MODIFY
    reason: The partner is another heat-shock protein (CRYAB), so heat shock protein binding is the appropriate specific molecular function.
    proposed_replacement_terms:
    - id: GO:0031072
      label: heat shock protein binding
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'Q16082; P02511: CRYAB; NbExp=3; IntAct=EBI-739395, EBI-739060'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26465331
  qualifier: enables
  review:
    summary: Cardiac yeast two-hybrid interactome again capturing the HSPB2-CRYAB interaction (and broader myofibrillar/mitochondrial clients). The sHSP-sHSP interaction is better captured as heat shock protein binding.
    action: MODIFY
    reason: Partner is the heat-shock protein CRYAB; heat shock protein binding is the specific molecular function. The wider client-binding role is captured by unfolded protein binding in core functions.
    proposed_replacement_terms:
    - id: GO:0031072
      label: heat shock protein binding
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'Q16082; P02511: CRYAB; NbExp=3; IntAct=EBI-739395, EBI-739060'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Large binary HuRI interactome screen capturing many heterogeneous partners (BAG3, A1CF, CEP19, POGZ, VEZF1 and others). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions; bare protein binding is not elevated to core and the partners are mostly unrelated to HSPB2's chaperone function.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'Q16082; O95817: BAG3; NbExp=5; IntAct=EBI-739395, EBI-747185'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome screen capturing an HSPB2-APP (amyloid precursor protein) interaction. Bare protein binding from a single high-throughput screen.
    action: KEEP_AS_NON_CORE
    reason: An isolated high-throughput interaction; uninformative bare protein binding, not part of the core muscle/chaperone function.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'Q16082; P05067: APP; NbExp=3; IntAct=EBI-739395, EBI-77613'
- 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 HSPB2-BAG3 interaction. BAG3 is a co-chaperone that cooperates with small HSPs; nonetheless this is a bare protein binding annotation.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with the sHSP co-chaperone BAG3 but as an uninformative bare-binding annotation; retained as non-core.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'Q16082; O95817: BAG3; NbExp=5; IntAct=EBI-739395, EBI-747185'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence localization to the nucleoplasm, consistent with the reported nuclear foci.
    action: ACCEPT
    reason: Direct antibody-based localization consistent with the documented nuclear pool.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: Note=Localizes to nuclear foci.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25556234
  qualifier: enables
  review:
    summary: AgBase-curated interaction (with P0DOE7) reported in a respiratory syncytial virus host-factor screen. Bare protein binding, unrelated to HSPB2's core function.
    action: KEEP_AS_NON_CORE
    reason: Isolated screen-derived interaction; uninformative bare protein binding.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-goa.tsv
      supporting_text: UniProtKB:P0DOE7
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:19464326
  qualifier: located_in
  review:
    summary: Direct experimental demonstration that HSPB2 localizes to the nucleus (nuclear foci).
    action: ACCEPT
    reason: Strongest-evidence nuclear localization.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: Note=Localizes to nuclear foci.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:19464326
  qualifier: located_in
  review:
    summary: Direct experimental demonstration that HSPB2 localizes to the cytoplasm.
    action: ACCEPT
    reason: Strongest-evidence cytoplasmic localization; principal site of HSPB2 action.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: NAS
  original_reference_id: PMID:9344664
  qualifier: involved_in
  review:
    summary: HSPB2 is an alpha-crystallin/small-HSP family member implicated in the stress response to unfolded proteins. Consistent with its holdase chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: A reasonable stress-response process annotation; the underlying molecular activity (binding non-native proteins) is the core feature captured by unfolded protein binding.
    supported_by:
    - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
      supporting_text: Belongs to the small heat shock protein (HSP20) family.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: PMID:9490724
  qualifier: located_in
  review:
    summary: Author-stated cytosolic localization; in muscle cytosol HSPB2/MKBP exists as an oligomeric complex distinct from the CRYAB/HSP27 complex.
    action: ACCEPT
    reason: Supported by the original MKBP characterization; cytosol is a principal site of HSPB2 oligomers.
    supported_by:
    - reference_id: PMID:9490724
      supporting_text: MKBP exists as an oligomeric complex separate from the complex
- term:
    id: GO:0008047
    label: enzyme activator activity
  evidence_type: TAS
  original_reference_id: PMID:9490724
  qualifier: enables
  review:
    summary: HSPB2/MKBP binds the myotonic dystrophy protein kinase (DMPK), enhances its kinase activity and protects it from heat-induced inactivation, acting as a kinase activator. This is a distinctive, well-documented HSPB2 function.
    action: ACCEPT
    reason: Directly demonstrated in vitro; HSPB2 enhances DMPK kinase activity, a genuine and specific enzyme-activator (kinase-activator) function.
    supported_by:
    - reference_id: PMID:9490724
      supporting_text: enhances the kinase activity of DMPK and protects it from heat-induced
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 based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservation of the subcellular location
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:9344664
  title: Identification and characterization of the gene encoding a new member of the alpha-crystallin/small hsp family, closely linked to the alphaB-crystallin gene in a head-to-head manner.
  findings: []
- id: PMID:9490724
  title: MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_9490724.md title matches; anchored to GOA as the TAS source for GO:0008047 (enzyme activator activity) and GO:0005829 (cytosol). Directly establishes the HSPB2/MKBP DMPK-binding-and-activation core function. Cited in core_functions supported_by."
  findings:
  - statement: HSPB2/MKBP is a small HSP that binds DMPK, enhances its kinase activity and protects it from heat-induced inactivation; it forms an oligomeric muscle-cytosol complex distinct from the alphaB-crystallin/HSP27 complex and is not induced by heat shock.
    reference_section_type: ABSTRACT
- id: PMID:14594798
  title: Interaction of human HSP22 (HSPB8) with other small heat shock proteins.
  findings: []
- id: PMID:19464326
  title: HSPB7 is a SC35 speckle resident small heat shock protein.
  findings:
  - statement: HSPB2 localizes to both the cytoplasm and the nucleus (nuclear foci).
    reference_section_type: RESULTS
- id: PMID:23188086
  title: 'Binding determinants of the small heat shock protein, αB-crystallin: recognition of the ''IxI'' motif.'
  findings: []
- id: PMID:25556234
  title: New host factors important for respiratory syncytial virus (RSV) replication revealed by a novel microfluidics screen for interactors of matrix (M) protein.
  findings: []
- id: PMID:26465331
  title: Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_26465331.md title matches; anchored to GOA as an IPI protein-binding source. Provides the validated GAPDH client and cardiac/mitochondrial interactome supporting the holdase (GO:0051082) core function. Cited in core_functions supported_by."
  findings:
  - statement: Cardiac HSPB2 overexpression is cardioprotective in ischemia (reduced infarct, maintained ATP); HSPB2 has a myofibrillar/mitochondrial cardiac interactome and GAPDH was validated as a client protein via chaperone assays.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: file:human/HSPB2/HSPB2-uniprot.txt
  title: UniProt entry Q16082 (HSPB2_HUMAN), Heat shock protein beta-2 (MKBP)
  findings:
  - statement: Small heat-shock protein (HSP20/alpha-crystallin family) expressed in skeletal muscle and heart but not lens; binds and may activate DMPK; localizes to cytoplasm and nucleus (nuclear foci).
    reference_section_type: OTHER
core_functions:
- description: ATP-independent small heat-shock protein (holdase) that binds non-native/destabilized client proteins via its alpha-crystallin domain to prevent their aggregation under stress, holding them for downstream refolding (validated client GAPDH).
  molecular_function:
    id: GO:0051082
    label: unfolded protein binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:26465331
    supporting_text: validated as a potential client protein of HspB2 through chaperone assays
  - reference_id: file:human/HSPB2/HSPB2-uniprot.txt
    supporting_text: Belongs to the small heat shock protein (HSP20) family.
- description: DMPK kinase activator; HSPB2/MKBP binds the myotonic dystrophy protein kinase, enhances its kinase activity and protects it from heat-induced inactivation, constituting a muscle stress-responsive system.
  molecular_function:
    id: GO:0008047
    label: enzyme activator activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:9490724
    supporting_text: enhances the kinase activity of DMPK and protects it from heat-induced
proposed_new_terms: []
suggested_questions:
- question: Does HSPB2 form a defined hetero-oligomer with HSPB3 in muscle, and how does this complex differ functionally from HSPB2 homo-oligomers and the CRYAB/HSP27 complex?
- question: Is DMPK activation a direct allosteric effect of HSPB2 binding, and is it disrupted in myotonic dystrophy where MKBP is selectively upregulated?
suggested_experiments:
- description: In vitro aggregation-protection (holdase) assays with recombinant HSPB2 against model and physiological clients (e.g. GAPDH) to quantify chaperone activity and ATP-independence.
- description: Reconstitute DMPK with HSPB2 to map the binding interface and measure kinase-activation kinetics, testing whether disease-associated changes alter activation.
- description: Define the muscle HSPB2/HSPB3 complex stoichiometry by size-exclusion/native MS and test client specificity relative to HSPB2 alone.

HSPB2

Gene Description