HdeB

id: P0AET2
gene_symbol: HdeB
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:83333
  label: Escherichia coli (strain K12)
description: HdeB is a periplasmic acid-stress chaperone in E. coli that functions
  as an ATP-independent holdase to prevent aggregation of periplasmic proteins under
  acidic conditions. It is a paralog of HdeA, and both proteins are encoded by the
  hdeAB acid stress operon. HdeB exists as a homodimer at neutral pH and dissociates
  into active monomers at acidic pH (complete dissociation at pH 3). While HdeA is
  more effective at pH 2, HdeB is more effective than HdeA at pH 3, and both are required
  for optimal protection against acid stress in vivo (PMID:17085547). HdeB exposes
  hydrophobic surfaces at acidic pH, consistent with its chaperone function. The protein
  is induced by the EvgS/EvgA two-component system and negatively regulated by H-NS
  and TorS/TorR.
existing_annotations:
- term:
    id: GO:0009268
    label: response to pH
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation via InterPro mapping. HdeB is indeed involved in the cellular
      response to pH, specifically acidic pH. This is a broader parent of the more
      specific GO:0010447 (response to acidic pH), which is already annotated with
      experimental evidence.
    action: ACCEPT
    reason: While this is a broader IEA term, it is not incorrect. HdeB is fundamentally
      a pH-responsive chaperone. The more specific term GO:0010447 is already annotated
      with IDA/IMP evidence, so this broader IEA is acceptable as a supporting annotation.
- term:
    id: GO:0042597
    label: periplasmic space
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for periplasmic space localization. This is consistent
      with the experimentally determined localization (IDA for GO:0030288, outer membrane-bounded
      periplasmic space). This IEA is a broader parent term.
    action: ACCEPT
    reason: Periplasmic localization is well established for HdeB. The more specific
      term GO:0030288 (outer membrane-bounded periplasmic space) is annotated with
      IDA. This broader IEA is acceptable.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation via InterPro mapping. HdeB does bind unfolded/aggregation-prone
      periplasmic proteins under acidic conditions. However, its function is better
      described as a holdase chaperone rather than simple binding.
    action: MODIFY
    reason: HdeB functions as an ATP-independent holdase that prevents aggregation
      of periplasmic proteins at acidic pH (PMID:17085547). The term GO:0051082 "unfolded
      protein binding" describes only the binding aspect, not the chaperone holdase
      function. GO:0140309 "unfolded protein carrier activity" (a protein carrier
      activity that binds to a protein in an unfolded state and escorts it, preventing
      aggregation) better captures the holdase function.
    proposed_replacement_terms:
    - id: GO:0051082
      label: unfolded protein binding (retain until holdase NTR is created)
    supported_by:
    - reference_id: PMID:17085547
      supporting_text: HdeB has a molecular mass of 10 kDa... HdeB is more efficient
        than HdeA in preventing periplasmic-protein aggregation [at pH 3]... we can
        conclude that Escherichia coli possesses two acid stress chaperones that prevent
        periplasmic-protein aggregation at acidic pH.
- term:
    id: GO:1990451
    label: cellular stress response to acidic pH
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: IEA annotation from UniRule transfer. HdeB is specifically involved in
      the cellular stress response to acidic pH, protecting periplasmic proteins from
      acid-induced aggregation. This term is appropriate and well-supported by the
      known biology.
    action: ACCEPT
    reason: This term accurately captures HdeB's role in the acid stress response.
      The protein functions specifically as an acid-activated chaperone (PMID:17085547).
    supported_by:
    - reference_id: PMID:17085547
      supporting_text: the hdeA and hdeB mutants both display reduced viability upon
        acid stress
- term:
    id: GO:0010447
    label: response to acidic pH
  evidence_type: IDA
  original_reference_id: PMID:17085547
  review:
    summary: IDA annotation based on direct experimental evidence from Kern et al.
      (2007). The study demonstrated that HdeB is an acid stress chaperone that prevents
      periplasmic protein aggregation at acidic pH, with optimal activity at pH 3.
    action: ACCEPT
    reason: Well-supported by direct experimental evidence. HdeB's chaperone activity
      is specifically activated at acidic pH and is required for protection against
      acid stress (PMID:17085547).
    supported_by:
    - reference_id: PMID:17085547
      supporting_text: HdeB is more efficient than HdeA in preventing periplasmic-protein
        aggregation [at pH 3]... HdeB, like HdeA, dissociates from dimers at neutral
        pH into monomers at acidic pHs, but its dissociation is complete at pH 3
- term:
    id: GO:0010447
    label: response to acidic pH
  evidence_type: IMP
  original_reference_id: PMID:17085547
  review:
    summary: IMP annotation based on mutant phenotype evidence. hdeB mutants display
      increased sensitivity to acid stress (PMID:17085547). This complements the IDA
      annotation for the same term.
    action: ACCEPT
    reason: The mutant phenotype clearly demonstrates HdeB's role in the acid stress
      response. hdeB deletion mutants show reduced viability at pH 2 and pH 3 (PMID:17085547).
    supported_by:
    - reference_id: PMID:17085547
      supporting_text: the hdeA and hdeB mutants both display reduced viability upon
        acid stress, and only the HdeA/HdeB expression plasmid can restore their viability
        to close to the wild-type level
- term:
    id: GO:0030288
    label: outer membrane-bounded periplasmic space
  evidence_type: IDA
  original_reference_id: PMID:17085547
  review:
    summary: IDA annotation for localization to the outer membrane-bounded periplasmic
      space. HdeB was extracted from bacteria by the osmotic-shock procedure, confirming
      its periplasmic localization (PMID:17085547). UniProt also confirms periplasm
      localization with a signal peptide (residues 1-29).
    action: ACCEPT
    reason: Directly supported by experimental evidence. HdeB has a signal peptide
      and was purified from the periplasm by osmotic shock (PMID:17085547).
    supported_by:
    - reference_id: PMID:17085547
      supporting_text: We extracted HdeB from bacteria by the osmotic-shock procedure
        and purified it to homogeneity by ion-exchange chromatography and hydroxyapatite
        chromatography.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:17085547
  review:
    summary: IDA annotation for unfolded protein binding based on direct experimental
      evidence. Kern et al. demonstrated that HdeB prevents aggregation of periplasmic
      proteins at acidic pH, consistent with binding unfolded proteins. However, the
      function is better described as holdase/chaperone activity rather than simple
      binding.
    action: MODIFY
    reason: While HdeB does bind unfolded proteins, its function is more accurately
      described as a holdase chaperone. GO:0140309 "unfolded protein carrier activity"
      better captures the ATP-independent holdase function that prevents aggregation
      and escorts substrates. The experimental evidence from PMID:17085547 demonstrates
      chaperone-like prevention of aggregation, not just binding.
    proposed_replacement_terms:
    - id: GO:0051082
      label: unfolded protein binding (retain until holdase NTR is created)
    supported_by:
    - reference_id: PMID:17085547
      supporting_text: At pH 3, however, HdeB is more efficient than HdeA in preventing
        periplasmic-protein aggregation. The solubilization of several model substrate
        proteins at acidic pH supports the hypothesis that, in vitro, HdeA plays a
        major role in protein solubilization at pH 2 and that both proteins are involved
        in protein solubilization at pH 3.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17085547
  title: Escherichia coli HdeB is an acid stress chaperone.
  findings:
  - statement: HdeB is a periplasmic acid stress chaperone
  - statement: HdeB is more effective than HdeA at pH 3
  - statement: Both HdeA and HdeB are required for optimal acid stress protection
  - statement: HdeB dissociates from dimers to monomers at acidic pH
- id: PMID:22138344
  title: Salt bridges regulate both dimer formation and monomeric flexibility in HdeB
    and may have a role in periplasmic chaperone function.
  findings:
  - statement: Structural basis for HdeB dimerization and monomer flexibility
core_functions:
- molecular_function:
    id: GO:0051082
    label: unfolded protein binding
  directly_involved_in:
  - id: GO:1990451
    label: cellular stress response to acidic pH
  locations:
  - id: GO:0030288
    label: outer membrane-bounded periplasmic space
  description: HdeB functions as an ATP-independent holdase chaperone that prevents
    aggregation of periplasmic proteins under acidic conditions. Optimal activity
    at pH 3-4. Dissociates from inactive dimers to active monomers at acidic pH.
  supported_by:
  - reference_id: PMID:17085547
    supporting_text: HdeB is more efficient than HdeA in preventing periplasmic-protein
      aggregation [at pH 3]