HSP26

id: P15992
gene_symbol: HSP26
product_type: PROTEIN
status: COMPLETE
tags:
- UPB
- sHSP
- holdase
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  HSP26 is the sole small heat shock protein (sHSP) of Saccharomyces cerevisiae, belonging to the
  conserved HSP20/alpha-crystallin superfamily. It functions as a temperature-regulated molecular
  chaperone with holdase activity: at heat shock temperatures, the 24-mer oligomeric storage complex
  dissociates, and the resulting smaller species bind non-native proteins to prevent their irreversible
  aggregation (PMID:10581247). This holdase activity is ATP-independent and mechanistically distinct
  from foldase chaperones (e.g., HSP70, GroEL). HSP26 does not actively refold substrates or escort
  them between compartments; rather, it maintains client proteins in a soluble, folding-competent state
  in situ until ATP-dependent chaperones (HSP70/HSP104) can mediate refolding. HSP26 forms large
  oligomeric complexes (>500 kD) and is induced by heat shock and other stress conditions. Its
  intracellular localization (cytoplasm vs. nucleus) varies with the metabolic state of the cell
  (PMID:2645298). HSP26 also localizes to stress granules during severe heat stress (PMID:24291094).
  Unexpectedly, Hsp26 was identified as a novel RNA-binding protein that co-purifies with a small set
  of specific mRNAs (PMID:20844764), though this activity is likely moonlighting rather than a core
  function.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation from ARBA machine learning models mapping HSP26 to protein folding. HSP26 is an
      sHSP holdase that prevents aggregation of unfolded proteins but does not actively assist protein
      folding (refolding requires the HSP70/HSP104 disaggregase system). The term "protein folding"
      (GO:0006457) implies active assistance in acquiring correct tertiary structure, which does not
      match HSP26 holdase mechanism. However, this IEA is broader than the IDA annotation for the same
      term (see below), and both share the same concern.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      HSP26 is a holdase, not a foldase. It prevents aggregation of non-native proteins but does not
      actively catalyze protein folding. The GO:0006457 definition states "assisting in the covalent
      and noncovalent assembly of single chain polypeptides or multisubunit complexes into the correct
      tertiary structure," which better describes ATP-dependent foldase chaperones like GroEL/ES or
      HSP70. HSP26 maintains substrates in a folding-competent state for later refolding by other
      chaperones. The IEA mapping is too generous here. A more appropriate BP annotation would be to a
      process term reflecting prevention of protein aggregation under stress.
    supported_by:
    - reference_id: PMID:10581247
      supporting_text: >-
        Hsp26, an sHsp from Saccharomyces cerevisiae, is a temperature-regulated molecular chaperone.
        Like other sHsps, Hsp26 forms large oligomeric complexes. At heat shock temperatures, however,
        the 24mer chaperone complex dissociates. ... Binding of non-native proteins to dissociated Hsp26
        produces large globular assemblies
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16429126
  review:
    summary: >-
      Protein binding annotation from the Gavin et al. (2006) large-scale TAP-tag affinity
      purification/mass spectrometry study of yeast protein complexes. HSP26 was identified as
      co-purifying with SSA2 (P10592) and VMA2 (P16140) in this study. While HSP26 does physically
      interact with proteins (both substrates and other chaperones), GO:0005515 "protein binding" is
      uninformative and does not capture the mechanistic nature of these interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 "protein binding" is too vague. For a chaperone like HSP26, the relevant molecular
      function is its holdase activity -- binding unfolded/misfolded proteins to prevent aggregation.
      The interactions detected in large-scale co-purification studies may reflect chaperone-substrate
      relationships (e.g., with SSA2, an HSP70 family member) or other associations. A more informative
      annotation would capture the holdase mechanism. Per curation guidelines, "protein binding" should
      be avoided in favor of more specific terms.
    supported_by:
    - reference_id: PMID:16429126
      supporting_text: >-
        Protein complexes are key molecular entities that integrate multiple gene products to perform
        cellular functions. Here we report the first genome-wide screen for complexes in an organism,
        budding yeast, using affinity purification and mass spectrometry.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554755
  review:
    summary: >-
      Protein binding annotation from Krogan et al. (2006) large-scale TAP-tag study of yeast protein
      complexes. Multiple interaction partners were detected (ADH3, EMW1, FUS3, NEW1, POL32, RNR1,
      RTT101, SGV1, SME1, TFB4, UPC2, VMA2). As a chaperone, HSP26 is expected to interact with many
      proteins, but GO:0005515 does not meaningfully describe the nature of these interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same rationale as above. GO:0005515 is uninformative for a chaperone. Many of these interaction
      partners may represent chaperone substrates or indirect associations from large-scale
      co-purification. HSP26 was classified as a "specific chaperone" with fewer than 200 non-chaperone
      interactors in the comprehensive chaperone atlas (PMID:19536198), consistent with its selective
      holdase function.
    supported_by:
    - reference_id: PMID:19536198
      supporting_text: >-
        the specific chaperones are (ordered from low to high number of interactors): Hsp32, Sno4,
        Hsp33, Tim14, Mdj2, Jac1, Cwc23, Jid1, Mcx1, Mdj1, Jjj2, Hlj1, Jjj3, Erj5, Ssc3, Kar2,
        Lhs1, Hsp26, Jem1, Jjj1, Xdj1, Hsp12, Hsp60
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19536198
  review:
    summary: >-
      Protein binding annotation from Gong et al. (2009), a comprehensive TAP-tag based chaperone
      interaction atlas covering all 63 yeast chaperones. HSP26 was classified as a "specific
      chaperone" with fewer than 200 interactors. Multiple interaction partners were detected. This
      study provides excellent systems-level context for HSP26 as a chaperone but GO:0005515 remains
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 does not capture the chaperone-substrate nature of these interactions. This study
      specifically characterizes HSP26 as a molecular chaperone with selective substrate binding. A more
      specific MF term reflecting holdase activity would be more appropriate.
    supported_by:
    - reference_id: PMID:19536198
      supporting_text: >-
        Molecular chaperones are defined as a group of highly interactive proteins that modulate the
        folding and unfolding of other proteins ... We expect that most of the chaperone interactors
        represent putative substrates whose conformational stability is modulated by molecular
        chaperones
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16843901
  review:
    summary: >-
      Identical protein binding annotation based on White et al. (2006), which used cryo-EM to
      characterize Hsp26 oligomeric assemblies. The study demonstrated that Hsp26 forms 24-subunit
      assemblies with tetrahedral symmetry, composed of asymmetric dimers, confirming self-association.
      This homo-oligomerization is integral to Hsp26 chaperone function.
    action: ACCEPT
    reason: >-
      HSP26 homo-oligomerization is well-established and functionally critical. The 24-mer complex
      is the storage form that dissociates at heat shock temperatures to become the active holdase
      species. The cryo-EM structural data directly demonstrates identical protein binding through
      dimer and trimer contacts. While GO:0042802 is somewhat generic, it correctly captures the
      self-association that is a defining structural feature of sHSPs.
    supported_by:
    - reference_id: PMID:16843901
      supporting_text: >-
        Cryo-electron microscopy of yeast Hsp26 reveals two distinct forms, each comprising 24
        subunits arranged in a porous shell with tetrahedral symmetry. The subunits form elongated,
        asymmetric dimers that assemble via trimeric contacts.
    - reference_id: PMID:10581247
      supporting_text: >-
        Like other sHsps, Hsp26 forms large oligomeric complexes. At heat shock temperatures, however,
        the 24mer chaperone complex dissociates.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18719252
  review:
    summary: >-
      Identical protein binding annotation from Yu et al. (2008), a high-quality binary yeast
      interactome study. HSP26-HSP26 self-interaction was detected, consistent with the known
      oligomeric nature of Hsp26.
    action: ACCEPT
    reason: >-
      This binary interaction study independently confirms HSP26 homo-oligomerization, which is
      consistent with the well-characterized 24-mer structure from cryo-EM (PMID:16843901). Duplicate
      evidence for the same GO term is appropriate when from independent experimental sources.
    supported_by:
    - reference_id: PMID:16843901
      supporting_text: >-
        Cryo-electron microscopy of yeast Hsp26 reveals two distinct forms, each comprising 24
        subunits arranged in a porous shell with tetrahedral symmetry.
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: HDA
  original_reference_id: PMID:26777405
  review:
    summary: >-
      HDA annotation from Jain et al. (2016) large-scale proteomic analysis of stress granule cores.
      This study used super-resolution microscopy and mass spectrometry to characterize stress granule
      composition, identifying molecular chaperones as conserved stress granule components.
    action: ACCEPT
    reason: >-
      Stress granule localization is consistent with HSP26 function as a stress-responsive chaperone.
      The Jain et al. study is a rigorous proteomic analysis of stress granule composition, and the
      finding is independently supported by direct IDA evidence from Cherkasov et al. (PMID:24291094),
      which showed heat stress granules contain molecular chaperones that coassemble with aggregates
      of misfolded proteins.
    supported_by:
    - reference_id: PMID:26777405
      supporting_text: >-
        Proteomic analysis of stress granule cores reveals a dense network of protein-protein
        interactions and links between stress granules and human diseases and identifies ATP-dependent
        helicases and protein remodelers as conserved stress granule components.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:24769239
  review:
    summary: >-
      HDA annotation from Renvoise et al. (2014) quantitative mitochondrial proteomics study. HSP26
      was detected in isolated mitochondrial fractions by mass spectrometry. However, HSP26 is
      primarily a cytoplasmic protein, and mitochondrial detection in large-scale proteomics may
      reflect contamination or transient association rather than bona fide mitochondrial localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSP26 is primarily cytoplasmic and nuclear (PMID:2645298), with stress granule localization
      under heat stress. Detection in mitochondrial fractions from a quantitative proteomics study
      could represent genuine low-level mitochondrial association (e.g., chaperoning mitochondrial
      surface proteins during stress) or co-purification artifact. UniProt does not list mitochondrial
      localization. This is not a core localization but may represent a minor or transient association,
      so it should be kept as non-core rather than removed.
    supported_by:
    - reference_id: PMID:24769239
      supporting_text: >-
        Label free quantitative analysis of protein accumulation revealed significant variation of 176
        mitochondrial proteins
    - reference_id: PMID:2645298
      supporting_text: >-
        When log-phase cells growing in glucose were heat shocked, hsp26 concentrated in nuclei ...
        in early stationary-phase cells hsp26 is induced at normal growth temperatures. This protein
        was generally distributed throughout the cells
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:11914276
  review:
    summary: >-
      HDA annotation from Kumar et al. (2002) proteome-wide subcellular localization study using
      epitope-tagged proteins and immunolocalization. HSP26 was detected in the cytoplasm.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established for HSP26 and is its primary localization. This
      is confirmed by multiple independent studies including direct IDA evidence (PMID:2645298) and
      the UniProt record. The large-scale localization study provides additional support.
    supported_by:
    - reference_id: PMID:11914276
      supporting_text: >-
        Here, we report the first proteome-scale analysis of protein localization within any eukaryote.
        ... we have determined the subcellular localization of 2744 yeast proteins.
    - reference_id: PMID:2645298
      supporting_text: >-
        in early stationary-phase cells hsp26 is induced at normal growth temperatures. This protein
        was generally distributed throughout the cells
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: IDA
  original_reference_id: PMID:24291094
  review:
    summary: >-
      IDA annotation from Cherkasov et al. (2013), which demonstrated that yeast heat stress granules
      contain molecular chaperones and coassemble with aggregates of misfolded proteins. The study
      showed that heat-SG disassembly requires Hsp104 and Hsp70 activity.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for HSP26 localization to stress granules during severe heat stress.
      This is mechanistically coherent with HSP26 holdase function, as stress granules form under
      conditions where protein aggregation occurs and translation is inhibited. The colocalization
      with misfolded protein aggregates is especially relevant to HSP26 chaperone activity.
    supported_by:
    - reference_id: PMID:24291094
      supporting_text: >-
        both S. cerevisiae and D. melanogaster heat-SGs contain mRNA, translation machinery components
        (excluding ribosomes), and molecular chaperones and that heat-SGs coassemble with aggregates
        of misfolded, heat-labile proteins
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IDA
  original_reference_id: PMID:10581247
  review:
    summary: >-
      IDA annotation from Haslbeck et al. (1999), the seminal study demonstrating HSP26 is a
      temperature-regulated chaperone. The study showed that Hsp26 chaperone activity is
      temperature-dependent: the 24-mer dissociates at heat shock temperatures, and this dissociation
      is a prerequisite for efficient chaperone activity.
    action: ACCEPT
    reason: >-
      HSP26 is one of the major proteins produced on heat shock (UniProt) and its chaperone activity
      is directly activated by elevated temperature through oligomer dissociation. This is a core
      biological process for HSP26 -- it is a heat shock protein whose functional activation is
      temperature-regulated. The evidence directly demonstrates temperature-dependent functional
      changes.
    supported_by:
    - reference_id: PMID:10581247
      supporting_text: >-
        Hsp26, an sHsp from Saccharomyces cerevisiae, is a temperature-regulated molecular chaperone.
        ... the dissociation of the Hsp26 complex at heat shock temperatures is a prerequisite for
        efficient chaperone activity
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:20844764
  review:
    summary: >-
      IDA annotation from Tsvetanova et al. (2010), a proteome-wide search for RNA-binding proteins
      using protein microarrays and IP-microarray validation. HSP26 was identified as a novel RBP that
      co-purified with 279 specific mRNAs (FDR less than 0.01%). The study describes HSP26 as a
      "chaperone; heat shock response" protein and notes it "co-purified with smaller sets of mRNAs,
      but these small sets of putative mRNA targets shared distinct functional and/or cytotopical
      themes." HSP26 lacks any known RNA-binding domain.
    action: KEEP_AS_NON_CORE
    reason: >-
      While the experimental evidence is sound (validated by IP-microarray with replicate experiments
      and stringent FDR cutoffs), mRNA binding is likely a moonlighting activity rather than a core
      function of HSP26. HSP26 lacks canonical RNA-binding domains, and the authors themselves describe
      it among "unexpected" RNA-binding proteins. The primary function of HSP26 is as a holdase
      chaperone for unfolded proteins. The mRNA binding may reflect the broad substrate-binding
      properties of chaperones, or a secondary regulatory role. Many chaperones have been found to
      associate with RNA in proteome-wide screens.
    supported_by:
    - reference_id: PMID:20844764
      supporting_text: >-
        Other candidate RBPs (Vtc1, Arc15, Hsp26, Arp8, Gis2) co-purified with smaller sets of
        mRNAs, but these small sets of putative mRNA targets shared distinct functional and/or
        cytotopical themes, increasing our confidence that the RNA-protein interactions we observed
        were genuine.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:2645298
  review:
    summary: >-
      IDA annotation from Rossi and Lindquist (1989), which showed that HSP26 intracellular
      localization varies with the metabolic state of the cell. In log-phase cells growing in glucose
      after heat shock, HSP26 concentrated in nuclei. However, this nuclear concentration was
      condition-dependent and did not occur in cells grown in galactose or acetate, or in
      mitochondrial mutants.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization of HSP26 is condition-dependent rather than constitutive. HSP26 concentrates
      in nuclei only in log-phase glucose-grown cells after heat shock; under other metabolic
      conditions it remains generally distributed throughout the cell. This represents a conditional
      localization rather than a core cellular component, so it should be retained but marked as
      non-core.
    supported_by:
    - reference_id: PMID:2645298
      supporting_text: >-
        When log-phase cells growing in glucose were heat shocked, hsp26 concentrated in nuclei and
        continued to concentrate in nuclei when these cells were returned to normal temperatures for
        recovery. However, hsp26 did not concentrate in nuclei under a variety of other conditions.
    - reference_id: PMID:2645298
      supporting_text: >-
        We conclude that the intracellular location of hsp26 in yeast depends upon the physiological
        state of the cell and not simply upon the presence or absence of heat stress.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:2645298
  review:
    summary: >-
      IDA annotation from Rossi and Lindquist (1989) demonstrating cytoplasmic localization of HSP26.
      The protein was generally distributed throughout the cytoplasm, particularly in stationary-phase
      cells and under most metabolic conditions.
    action: ACCEPT
    reason: >-
      Cytoplasm is the primary and constitutive localization of HSP26. Under most physiological
      conditions, HSP26 is distributed throughout the cytoplasm. This is the core cellular component
      for HSP26 function as a cytoplasmic holdase chaperone.
    supported_by:
    - reference_id: PMID:2645298
      supporting_text: >-
        in early stationary-phase cells hsp26 is induced at normal growth temperatures. This protein
        was generally distributed throughout the cells, even after heat shock.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:10581247
  review:
    summary: >-
      IDA annotation from Haslbeck et al. (1999) based on in vitro chaperone assays demonstrating
      that Hsp26 protects proteins from irreversible aggregation. The term "protein folding" is
      applied here, but the actual experimental evidence shows holdase activity (aggregation
      prevention), not active refolding. sHSPs maintain substrates in a folding-competent state
      but require HSP70/HSP104 for actual refolding.
    action: MODIFY
    reason: >-
      The experimental evidence in PMID:10581247 demonstrates that HSP26 prevents irreversible
      aggregation of non-native proteins. This is holdase activity, not protein folding per se.
      GO:0006457 "protein folding" implies active assistance in acquiring correct tertiary structure,
      which better describes ATP-dependent foldases. HSP26 functions upstream of refolding by
      maintaining substrates in a soluble, folding-competent state. A more accurate BP annotation
      would be "chaperone-mediated protein complex assembly" (GO:0051131) or ideally a BP term for
      "prevention of protein aggregation," though no such specific term currently exists. As an
      interim measure, "protein folding" is overly generous but not entirely wrong since HSP26
      participates in the broader proteostasis pathway that includes folding.
    proposed_replacement_terms:
    - id: GO:0051131
      label: chaperone-mediated protein complex assembly
    supported_by:
    - reference_id: PMID:10581247
      supporting_text: >-
        Several sHsps have been shown to exhibit chaperone activity and protect proteins from
        irreversible aggregation in vitro. ... Binding of non-native proteins to dissociated Hsp26
        produces large globular assemblies ... In this complex one monomer of substrate is bound per
        Hsp26 dimer.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:10581247
  review:
    summary: >-
      IDA annotation from Haslbeck et al. (1999), the key study demonstrating HSP26 chaperone
      activity. The study showed that at heat shock temperatures, Hsp26 24-mer dissociates and the
      resulting active species binds non-native proteins, forming large chaperone-substrate complexes
      with a 1:2 substrate:Hsp26 stoichiometry. This is canonical holdase activity: binding
      unfolded/misfolded proteins to prevent their irreversible aggregation, without actively
      catalyzing refolding. HSP26 is ATP-independent and does not escort substrates between cellular
      compartments. Per the UPB project, GO:0051082 is proposed for obsoletion
      (go-ontology#30962). The appropriate replacement is a general "holdase chaperone activity" NTR.
      GO:0140309 "unfolded protein carrier activity" does NOT fit because it was created specifically
      for TIM carrier-holdases that escort proteins between compartments (go-ontology#30552), and
      HSP26 is an in-situ holdase.
    action: MODIFY
    reason: >-
      HSP26 is a canonical in-situ holdase chaperone. GO:0051082 "unfolded protein binding" is
      proposed for obsoletion and is too vague -- it is a binding term that does not distinguish
      holdase from foldase from sensor mechanisms. The best replacement would be the proposed "holdase
      chaperone activity" NTR (an activity term for ATP-independent prevention of protein aggregation
      in situ). GO:0140309 "unfolded protein carrier activity" does NOT fit because (1) its definition
      requires escort "between two different cellular components," (2) it is a child of GO:0140597
      "protein carrier chaperone," and (3) HSP26 prevents aggregation in situ without transporting
      substrates between compartments. Until the holdase NTR is created, GO:0051082 should be retained
      as an interim annotation. GO:0044183 "protein folding chaperone" is also inappropriate because
      HSP26 does not actively fold proteins.
    proposed_replacement_terms:
    - id: NTR
      label: holdase chaperone activity (NTR needed; GO:0140309 does not fit -- carrier-specific)
    additional_reference_ids:
    - go-ontology#30962
    - go-ontology#30552
    supported_by:
    - reference_id: PMID:10581247
      supporting_text: >-
        Several sHsps have been shown to exhibit chaperone activity and protect proteins from
        irreversible aggregation in vitro. Here we show that Hsp26, an sHsp from Saccharomyces
        cerevisiae, is a temperature-regulated molecular chaperone.
    - reference_id: PMID:10581247
      supporting_text: >-
        Binding of non-native proteins to dissociated Hsp26 produces large globular assemblies with a
        structure that appears to be completely reorganized relative to the original Hsp26 oligomers.
        In this complex one monomer of substrate is bound per Hsp26 dimer.
    - reference_id: PMID:16843901
      supporting_text: >-
        Hinge points between the domains allow a variety of assembly contacts, providing the
        flexibility required for formation of supercomplexes with non-native proteins.
references:
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10581247
  title: 'Hsp26: a temperature-regulated chaperone.'
  findings:
  - statement: >-
      HSP26 is a temperature-regulated molecular chaperone. The 24-mer storage complex dissociates at
      heat shock temperatures, and this dissociation is a prerequisite for efficient chaperone activity.
      Binding of non-native proteins to dissociated Hsp26 produces large globular assemblies with 1:2
      substrate:Hsp26 stoichiometry.
- id: PMID:11914276
  title: Subcellular localization of the yeast proteome.
  findings:
  - statement: >-
      Large-scale immunolocalization study of 2744 yeast proteins. HSP26 detected in cytoplasm.
- id: PMID:16429126
  title: Proteome survey reveals modularity of the yeast cell machinery.
  findings:
  - statement: >-
      Genome-wide TAP-tag affinity purification/MS screen for yeast protein complexes. HSP26 detected
      as co-purifying with SSA2 and VMA2.
- id: PMID:16554755
  title: Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
  findings:
  - statement: >-
      Large-scale TAP-tag study of yeast protein complexes. Multiple HSP26 interaction partners
      detected including ADH3, EMW1, FUS3, NEW1, POL32, RNR1, RTT101, SGV1, SME1, TFB4, UPC2, VMA2.
- id: PMID:16843901
  title: Multiple distinct assemblies reveal conformational flexibility in the small
    heat shock protein Hsp26.
  findings:
  - statement: >-
      Cryo-EM structure of Hsp26 reveals two distinct 24-subunit forms with tetrahedral symmetry.
      Subunits form asymmetric dimers that assemble via trimeric contacts. C-terminal tails form
      3-fold contacts. Hinge points between domains provide flexibility for supercomplex formation
      with non-native proteins.
- id: PMID:18719252
  title: High-quality binary protein interaction map of the yeast interactome network.
  findings:
  - statement: >-
      High-quality binary yeast interactome. HSP26-HSP26 self-interaction confirmed.
- id: PMID:19536198
  title: 'An atlas of chaperone-protein interactions in Saccharomyces cerevisiae:
    implications to protein folding pathways in the cell.'
  findings:
  - statement: >-
      Comprehensive TAP-tag analysis of all 63 yeast chaperones. HSP26 classified as a "specific"
      chaperone with fewer than 200 non-chaperone interactors, consistent with selective holdase
      function rather than promiscuous chaperoning.
- id: PMID:20844764
  title: Proteome-wide search reveals unexpected RNA-binding proteins in Saccharomyces
    cerevisiae.
  findings:
  - statement: >-
      HSP26 identified as novel RNA-binding protein by protein microarray screen and validated by
      IP-microarray. Co-purified with 279 specific mRNAs. Lacks known RNA-binding domain. Described
      among "unexpected" RBPs with "day jobs" as enzymes or chaperones.
- id: PMID:24291094
  title: Coordination of translational control and protein homeostasis during severe
    heat stress.
  findings:
  - statement: >-
      Yeast heat stress granules contain mRNA, translation machinery, and molecular chaperones.
      Heat-SGs coassemble with aggregates of misfolded proteins. Disassembly requires Hsp104 and
      Hsp70 activity.
- id: PMID:24769239
  title: Quantitative variations of the mitochondrial proteome and phosphoproteome
    during fermentative and respiratory growth in Saccharomyces cerevisiae.
  findings:
  - statement: >-
      Quantitative mitochondrial proteomics detected HSP26 in isolated mitochondrial fractions.
- id: PMID:2645298
  title: The intracellular location of yeast heat-shock protein 26 varies with metabolism.
  findings:
  - statement: >-
      HSP26 found in complexes >500 kD. Intracellular localization depends on metabolic state: in
      glucose-grown log-phase cells after heat shock, concentrates in nuclei; in stationary-phase
      cells or cells grown in galactose/acetate, distributed throughout cytoplasm.
- id: PMID:26777405
  title: ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure.
  findings:
  - statement: >-
      Proteomic analysis of stress granule cores reveals molecular chaperones as conserved components.
      ATP is required for stress granule assembly and dynamics.
core_functions:
- description: >-
    HSP26 is an ATP-independent holdase chaperone that binds unfolded/misfolded proteins to prevent
    their irreversible aggregation. At heat shock temperatures, the 24-mer storage complex
    dissociates into active species that bind non-native proteins with 1:2 substrate:Hsp26
    stoichiometry. This is the core molecular function of HSP26. GO:0051082 is used as interim until
    a holdase NTR is created; GO:0140309 does not fit (carrier-specific). GO:0044183 does not fit
    (HSP26 does not actively refold).
  molecular_function:
    id: GO:0051082
    label: unfolded protein binding
  directly_involved_in:
  - id: GO:0034605
    label: cellular response to heat
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:10581247
    supporting_text: >-
      Hsp26, an sHsp from Saccharomyces cerevisiae, is a temperature-regulated molecular chaperone.
      ... Binding of non-native proteins to dissociated Hsp26 produces large globular assemblies
  - reference_id: PMID:16843901
    supporting_text: >-
      Hinge points between the domains allow a variety of assembly contacts, providing the
      flexibility required for formation of supercomplexes with non-native proteins.
- description: >-
    HSP26 forms large homo-oligomeric 24-mer complexes with tetrahedral symmetry. Self-association
    is essential for its chaperone function: the 24-mer serves as a storage/inactive form, and
    temperature-dependent dissociation produces the active holdase species.
  molecular_function:
    id: GO:0042802
    label: identical protein binding
  supported_by:
  - reference_id: PMID:16843901
    supporting_text: >-
      Cryo-electron microscopy of yeast Hsp26 reveals two distinct forms, each comprising 24
      subunits arranged in a porous shell with tetrahedral symmetry.
  - reference_id: PMID:10581247
    supporting_text: >-
      the 24mer chaperone complex dissociates ... the dissociation of the Hsp26 complex at heat
      shock temperatures is a prerequisite for efficient chaperone activity
proposed_new_terms:
- proposed_name: holdase chaperone activity
  proposed_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. This is mechanistically distinct from foldase activity (GO:0044183) and from carrier-
    holdase activity (GO:0140309).
  justification: >-
    HSP26 and other sHSPs (CRYAA, CRYAB, HSPB6 in human) are canonical in-situ holdases that
    cannot be properly annotated with existing GO terms. GO:0051082 is proposed for obsoletion,
    GO:0044183 implies active refolding, and GO:0140309 is carrier-specific. See UPB project and
    go-ontology#30552.
  supported_by:
  - reference_id: PMID:10581247
    supporting_text: >-
      Several sHsps have been shown to exhibit chaperone activity and protect proteins from
      irreversible aggregation in vitro. Here we show that Hsp26, an sHsp from Saccharomyces
      cerevisiae, is a temperature-regulated molecular chaperone.
suggested_questions:
- question: What are the specific substrate proteins that HSP26 binds during heat shock in vivo?
- question: Does HSP26 mRNA binding activity (PMID:20844764) have a physiological role, or is it an artifact of the broad substrate-binding properties of chaperones?
- question: How does HSP26 holdase activity coordinate with HSP104 disaggregase and HSP70 foldase during stress recovery?
- question: Is the temperature-dependent oligomer dissociation mechanism conserved across yeast sHSPs (e.g., Hsp42)?