hsp-12.3

id: Q20164
gene_symbol: hsp-12.3
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  C. elegans HSP-12.3 is a 12.3 kDa member of the small heat shock protein (sHSP/HSP20)
  family. It contains an alpha-crystallin domain (SHSP domain) but has an unusually
  short N-terminal region and lacks a C-terminal tail, making it one of the smallest
  known sHSPs. Recombinant HSP-12.3 forms tetramers rather than the large oligomeric
  complexes typical of other sHSPs, and critically, it lacks detectable in vitro
  chaperone-like activity (PMID:9744800). This distinguishes it from canonical sHSPs
  that function as holdase chaperones. HSP-12.3 physically interacts with HSP-12.2
  (PMID:9744800). The protein is associated with reproductive tissues including vulva
  and spermatheca (PMID:11001875). Despite lacking chaperone activity in vitro, C.
  elegans 12 kDa sHSPs play roles in dauer formation, longevity, and reproduction
  in vivo. The PMID:9744800 study concludes that tetramers are the building blocks
  of sHSP complexes and that higher multimer formation, mediated through the N-terminal
  domains, is a prerequisite for chaperone-like activity.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasmic localization, inferred phylogenetically from
      a large set of sHSP orthologs across fly, worm, mouse, rat, human, and
      zebrafish species. The inference is phylogenetically well-supported. sHSPs
      are generally cytoplasmic proteins, and immunohistochemical data in C. elegans
      shows HSP12 proteins in vulva and spermatheca tissue (PMID:11001875).
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established for sHSP family proteins. The
      IBA inference from multiple orthologs is phylogenetically sound and consistent
      with immunohistochemical localization data in C. elegans (PMID:11001875).
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for nuclear localization based on phylogenetic inference from
      mammalian sHSP orthologs including CRYAA, CRYAB, HSP27/HSPB1 that have been
      reported to translocate to the nucleus under stress conditions. Nuclear
      localization is not the primary compartment for sHSPs and has not been
      specifically demonstrated for C. elegans HSP-12.3.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear localization has been reported for some mammalian sHSP orthologs. The
      IBA inference is phylogenetically supported but represents a secondary or
      stress-dependent localization. Not the primary compartment for sHSP function.
      Retained as non-core.
- term:
    id: GO:0009408
    label: response to heat
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for involvement in heat stress response, inferred
      phylogenetically from a large set of sHSP orthologs across fly, worm, and
      zebrafish. HSP-12.3 is classified as a heat shock protein (HSP20 family),
      and while its in vivo response to heat has not been specifically characterized,
      its classification as an sHSP and the IBA inference from well-characterized
      orthologs support this annotation.
    action: ACCEPT
    reason: >-
      HSP-12.3 is a member of the sHSP/HSP20 family which is fundamentally involved
      in heat stress response. The IBA inference from multiple sHSP orthologs is
      phylogenetically well-supported. Response to heat is a core function of the
      sHSP family even if the mechanism differs from canonical chaperone activity.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein refolding, inferred phylogenetically primarily from
      Drosophila sHSP orthologs. However, HSP-12.3 has been experimentally demonstrated
      to lack chaperone-like activity in vitro (PMID:9744800). Kokke et al. showed that
      recombinant HSP-12.3 forms tetramers and is devoid of in vitro chaperone-like
      abilities. The authors concluded that higher multimer formation, mediated through
      the N-terminal domains that HSP-12.3 lacks, is a prerequisite for chaperone-like
      activity. This annotation is therefore incorrect for HSP-12.3.
    action: REMOVE
    reason: >-
      HSP-12.3 has been directly demonstrated to lack chaperone-like activity in vitro
      (PMID:9744800). It forms tetramers rather than the large oligomeric complexes
      required for chaperone function. The IBA inference from Drosophila sHSP orthologs
      does not apply because HSP-12.3 has divergent structural properties (very short
      N-terminal region, no C-terminal tail) that preclude holdase/chaperone activity.
      There is also a NOT annotation for GO:0051082 (unfolded protein binding) from the
      same publication confirming this.
    supported_by:
      - reference_id: PMID:9744800
        supporting_text: >-
          both appear devoid of in vitro chaperone-like abilities. This supports the
          notion that tetramers are the building blocks of sHSP complexes, and that
          higher multimer formation, mediated through the N-terminal domains, is a
          prerequisite for chaperone-like activity.
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IPI
  original_reference_id: PMID:9744800
  review:
    summary: >-
      IPI annotation for heat shock protein binding based on Kokke et al. 1998
      (PMID:9744800). The study demonstrated physical interaction between HSP-12.3
      and HSP-12.2 (WB:WBGene00002011), both of which are 12 kDa sHSPs that form
      tetramers. This represents homotypic interaction within the sHSP family.
    action: ACCEPT
    reason: >-
      The physical interaction between HSP-12.3 and HSP-12.2 is directly demonstrated
      by experimental evidence (PMID:9744800). Heat shock protein binding accurately
      captures this interaction between sHSP family members. This is a core molecular
      function for HSP-12.3.
    supported_by:
      - reference_id: PMID:9744800
        supporting_text: >-
          they are the first sHSPs shown to occur as tetramers, rather than forming
          the usual large multimeric complexes
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:9744800
  negated: true
  review:
    summary: >-
      NOT annotation (negated IDA) for unfolded protein binding based on Kokke et al.
      1998 (PMID:9744800). The study directly tested recombinant HSP-12.3 for
      chaperone-like activity and found it devoid of the ability to prevent aggregation
      of denaturing substrate proteins. This negative result is consistent with the
      structural analysis showing that HSP-12.3 forms tetramers rather than the large
      oligomeric complexes required for chaperone function. GO:0051082 is proposed for
      obsoletion, but the negation is still informative as it indicates this protein
      does not have holdase activity.
    action: ACCEPT
    reason: >-
      This NOT annotation is an important negative result directly demonstrated by
      experimental evidence (PMID:9744800). HSP-12.3 lacks chaperone-like activity
      and does not bind unfolded proteins in the functional sense despite being an
      sHSP family member. The negation correctly documents this experimentally
      determined absence of function.
    supported_by:
      - reference_id: PMID:9744800
        supporting_text: >-
          [Both HSP-12.2 and HSP-12.3 are] devoid of in vitro chaperone-like abilities.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: PMID:9744800
  title: Caenorhabditis elegans small heat-shock proteins Hsp12.2 and Hsp12.3 form
    tetramers and have no chaperone-like activity.
  findings:
    - statement: >-
        Recombinant C. elegans HSP-12.2 and HSP-12.3 form tetramers, making them
        the first sHSPs shown to occur as tetramers. Both are devoid of in vitro
        chaperone-like abilities. These proteins have very short N-terminal regions
        and lack C-terminal tails. The authors conclude that higher multimer
        formation, mediated through N-terminal domains, is a prerequisite for
        chaperone-like activity.
      supporting_text: >-
        both appear devoid of in vitro chaperone-like abilities. This supports the
        notion that tetramers are the building blocks of sHSP complexes, and that
        higher multimer formation, mediated through the N-terminal domains, is a
        prerequisite for chaperone-like activity.
- id: PMID:11001875
  title: Association of several small heat-shock proteins with reproductive tissues
    in the nematode Caenorhabditis elegans.
  findings:
    - statement: >-
        Immunohistochemical analysis shows that HSP12 proteins are expressed in
        vulva and spermatheca of C. elegans.
      supporting_text: >-
        the tissues expressing the greatest number of smHSPs are vulva (HSP12s,
        HSP43 and, under stress, HSP16s) and spermatheca (HSP12s, HSP25, HSP43
        and, under stress, HSP16s).
core_functions:
  - molecular_function:
      id: GO:0031072
      label: heat shock protein binding
    directly_involved_in:
      - id: GO:0009408
        label: response to heat
    locations:
      - id: GO:0005737
        label: cytoplasm
    description: >-
      HSP-12.3 is an atypical sHSP that forms tetramers and physically interacts
      with HSP-12.2 (PMID:9744800). Unlike canonical sHSPs, it lacks chaperone-like
      activity in vitro due to its very short N-terminal region and absence of
      C-terminal tail, which prevents higher-order oligomerization required for
      holdase function (PMID:9744800). Its role in the heat stress response may
      involve protein-protein interactions with other sHSP family members rather
      than direct substrate holdase activity.