cryaba

id: Q9PUR2
gene_symbol: cryaba
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:7955
  label: Danio rerio
description: >-
  Zebrafish alpha-crystallin B chain a (cryaba, also known as cryab or alphaB1-crystallin)
  is a member of the small heat shock protein (sHSP/HSP20) family. It is one of two
  zebrafish alphaB-crystallin paralogs arising from the teleost whole-genome duplication,
  with cryaba being the lens-specific paralog and cryabb retaining the broad expression
  pattern of mammalian CRYAB (PMID:16420472). cryaba is predominantly expressed in the
  lens with lower expression in heart, brain, skeletal muscle, and liver (PMID:16420472).
  In the lens, cryaba localizes around the entire fiber cell membrane producing a
  honeycomb appearance (PMID:18406404). Recombinant cryaba (alphaB1-crystallin) has
  reduced chaperone-like activity compared to human CRYAB, particularly at higher
  temperatures, though it retains some chaperone activity at 25-30 degrees C
  (PMID:15692462, PMID:16420472). Loss of cryaba increases age-related cataract in
  zebrafish, with cryaba null fish showing greater lens opacity at 24 months than
  cryaa null fish (PMID:38705506). Single-cell RNA-seq and RT-qPCR data show an
  ontogenetic shift in alpha-crystallin usage, with cryaa predominating at 5-6 dpf
  and cryaba becoming more important after 10 dpf (PMID:38705506). cryaba makes up
  approximately 0.16% of total zebrafish lens protein (PMID:16420472). Morpholino
  knockdown of cryaba causes skeletal muscle defects, myofibril disassembly, heart
  failure, and locomotory impairment in zebrafish embryos (PMID:25866181). The protein
  contains zinc-binding residues at positions 101, 103, and 108.
existing_annotations:
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation based on phylogenetic inference from mammalian alpha-crystallins
      (CRYAA, CRYAB, HSPB1) which have documented anti-apoptotic roles. The
      anti-apoptotic function of alpha-crystallins is well-established for mammalian
      orthologs. While not directly demonstrated for zebrafish cryaba, the phylogenetic
      inference is reasonable. However, this is not a core molecular function of cryaba
      but rather a downstream biological process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Anti-apoptotic activity is a recognized function of the sHSP family but represents
      a downstream biological process rather than a core molecular function. The IBA
      inference from mammalian CRYAB orthologs is phylogenetically sound. Retained as
      non-core since the primary function is structural role in the lens and holdase
      activity.
- 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
      multiple sHSP orthologs across fly, worm, mouse, rat, human, and zebrafish.
      Consistent with the known biology of alpha-crystallins as cytoplasmic proteins
      in lens fiber cells.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established for alpha-crystallins. cryaba is
      a cytoplasmic protein in lens fiber cells. The IBA inference is consistent with
      established biology and IEA annotations.
- 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 sHSPs that translocate to the nucleus under stress conditions. Nuclear
      localization is not the primary site of action for alpha-crystallins.
    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. 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 heat stress response, inferred phylogenetically from
      multiple sHSP orthologs. cryaba belongs to the sHSP/HSP20 family and retains
      some chaperone-like activity (PMID:16420472), consistent with a role in heat
      stress response.
    action: ACCEPT
    reason: >-
      cryaba is a member of the sHSP family which is fundamentally involved in heat
      stress response. The IBA inference from multiple orthologs is phylogenetically
      well-supported. Though cryaba has reduced chaperone activity compared to
      mammalian CRYAB, it retains measurable activity (PMID:16420472).
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein refolding, inferred primarily from Drosophila sHSP
      orthologs. Alpha-crystallins function as holdases rather than foldases -- they
      prevent aggregation of denaturing proteins but do not actively refold them.
      cryaba has reduced but measurable chaperone-like (holdase) activity
      (PMID:15692462, PMID:16420472). The protein refolding term is inaccurate for
      a holdase.
    action: MODIFY
    reason: >-
      Alpha-crystallins are holdase chaperones that prevent aggregation of unfolded
      proteins but do not catalyze refolding. GO:0042026 implies active refolding
      activity, which is inaccurate for cryaba. GO:0140309 (unfolded protein carrier
      activity) is not appropriate because it is carrier-specific (per
      go-ontology#30552). Retain until a holdase chaperone activity NTR is created.
    proposed_replacement_terms:
      - id: GO:0051082
        label: unfolded protein binding (retain until holdase NTR is created)
    supported_by:
      - reference_id: PMID:15692462
        supporting_text: >-
          The chaperone-like activities of the two zebrafish alpha-crystallins were
          highly divergent, with alphaA-crystallin showing much greater activity than
          alphaB-crystallin.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for unfolded protein binding based on phylogenetic inference from
      multiple alpha-crystallin and sHSP orthologs. GO:0051082 is proposed for
      obsoletion. cryaba has been demonstrated to have some chaperone-like activity,
      particularly at lower temperatures (PMID:16420472). The holdase function should
      be captured by GO:0140309.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. The holdase activity of cryaba, though
      reduced compared to mammalian CRYAB, has been demonstrated by in vitro
      chaperone assays (PMID:15692462, PMID:16420472). GO:0140309 (unfolded protein
      carrier activity) is not appropriate because it is carrier-specific (per
      go-ontology#30552). Retain until a holdase chaperone activity NTR is created.
    proposed_replacement_terms:
      - id: GO:0051082
        label: unfolded protein binding (retain until holdase NTR is created)
    supported_by:
      - reference_id: PMID:16420472
        supporting_text: >-
          At 25 degrees C and 30 degrees C, zebrafish alphaB2 showed greater
          chaperone-like activity than human alphaB-crystallin, and at 35 degrees C
          and 40 degrees C, the human protein provided greater protection against
          aggregation.
- term:
    id: GO:0005212
    label: structural constituent of eye lens
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation based on InterPro domain match (IPR003090 Alpha-crystallin_N)
      and UniProt keyword (KW-0273 Eye lens protein). Alpha-crystallins are major
      structural proteins of the vertebrate lens. cryaba is predominantly expressed
      in the lens (PMID:16420472) and its loss increases age-related cataract
      (PMID:38705506).
    action: ACCEPT
    reason: >-
      Structural role in the eye lens is a well-established core function of
      alpha-crystallins. cryaba is predominantly lens-expressed and its loss leads
      to increased age-related cataract (PMID:38705506). The IEA inference is
      correct and supported by direct experimental data.
    supported_by:
      - reference_id: PMID:38705506
        supporting_text: >-
          we found that the loss of the alphaBa-crystallin gene cryaba led to an
          increase in lens opacity compared to cryaa null fish at 24 months of age.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for cytoplasmic localization based on ARBA machine learning
      models. Consistent with the IBA annotation for the same term and the
      established biology of alpha-crystallins as cytoplasmic proteins.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established. This IEA annotation is consistent
      with the IBA annotation. Acceptable as automated confirmation.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation based on UniProt keyword mapping (KW-0479 Metal-binding). The
      UniProt entry annotates zinc-binding residues at positions 101, 103, and 108
      based on PIRSR evidence (PIRSR036514-1). While the annotation to GO:0046872
      (metal ion binding) is technically correct, it is very general. The more
      specific term GO:0008270 (zinc ion binding) would be more informative given
      the specific zinc-binding sites annotated.
    action: MODIFY
    reason: >-
      The annotation is too general. UniProt annotates specific zinc-binding residues
      at positions 101, 103, and 108, indicating zinc ion binding rather than generic
      metal ion binding. A more specific term would be more informative.
    proposed_replacement_terms:
      - id: GO:0008270
        label: zinc ion binding
- term:
    id: GO:0036438
    label: maintenance of lens transparency
  evidence_type: IMP
  original_reference_id: PMID:38705506
  review:
    summary: >-
      IMP annotation for maintenance of lens transparency based on Posner et al. 2024
      (PMID:38705506). The study used individual mutant zebrafish lines for all three
      alpha-crystallin genes and found that loss of cryaba led to an increase in lens
      opacity compared to cryaa null fish at 24 months of age. This is the first study
      to show that cryaba plays a leading role in preventing age-related cataract in
      zebrafish.
    action: ACCEPT
    reason: >-
      Strong experimental evidence demonstrating that cryaba loss increases age-related
      cataract in zebrafish (PMID:38705506). This is a core biological process for
      cryaba, directly linked to its structural and chaperone roles in the lens.
    supported_by:
      - reference_id: PMID:38705506
        supporting_text: >-
          we found that the loss of the alphaBa-crystallin gene cryaba led to an
          increase in lens opacity compared to cryaa null fish at 24 months of age.
      - reference_id: PMID:38705506
        supporting_text: >-
          Our finding that the lens-specific zebrafish alphaBa-crystallin plays the
          leading role in preventing age-related cataract adds a new twist to our
          understanding of vertebrate lens evolution.
- term:
    id: GO:0007519
    label: skeletal muscle tissue development
  evidence_type: IMP
  original_reference_id: PMID:25866181
  review:
    summary: >-
      IMP annotation for skeletal muscle tissue development based on Buhrdel et al.
      2015 (PMID:25866181). The study used morpholino-mediated knockdown of MFM
      (myofibrillar myopathy) disease genes in zebrafish, including cryaba (which
      is the zebrafish ortholog of human CRYAB, a known MFM gene). Knockdown led to
      compromised skeletal muscle function due to myofibrillar degeneration. This
      reflects a role in muscle maintenance rather than a core lens function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The morpholino knockdown evidence (PMID:25866181) supports a role in skeletal
      muscle tissue development/maintenance, consistent with the broader sHSP family
      role in muscle. However, unlike mammalian CRYAB which is broadly expressed in
      muscle, zebrafish cryaba is predominantly lens-specific (PMID:16420472), making
      this a secondary function. Retained as non-core.
    supported_by:
      - reference_id: PMID:25866181
        supporting_text: >-
          targeted ablation of MFM genes in zebrafish led to compromised skeletal
          muscle function mostly due to myofibrillar degeneration as well as severe
          heart failure.
- term:
    id: GO:0007626
    label: locomotory behavior
  evidence_type: IMP
  original_reference_id: PMID:25866181
  review:
    summary: >-
      IMP annotation for locomotory behavior based on Buhrdel et al. 2015
      (PMID:25866181). Morpholino knockdown of cryaba led to compromised skeletal
      muscle function which would affect locomotion. This is a downstream consequence
      of the muscle defect rather than a direct role in locomotory behavior.
    action: KEEP_AS_NON_CORE
    reason: >-
      The locomotory behavior phenotype from cryaba knockdown (PMID:25866181) is a
      downstream consequence of myofibrillar degeneration rather than a direct role
      in locomotion. This is a non-core function for a predominantly lens-specific
      protein.
- term:
    id: GO:0030239
    label: myofibril assembly
  evidence_type: IMP
  original_reference_id: PMID:25866181
  review:
    summary: >-
      IMP annotation for myofibril assembly based on Buhrdel et al. 2015
      (PMID:25866181). Morpholino knockdown of cryaba led to myofibrillar
      degeneration. This is consistent with the known role of mammalian CRYAB
      in maintaining myofibrillar integrity, but zebrafish cryaba is predominantly
      lens-specific rather than muscle-expressed.
    action: KEEP_AS_NON_CORE
    reason: >-
      The myofibrillar degeneration phenotype from cryaba knockdown (PMID:25866181)
      supports a role in myofibril assembly/maintenance. However, zebrafish cryaba
      is predominantly lens-specific (PMID:16420472), making this a secondary function.
      The muscle-associated function may be more attributable to cryabb which retains
      broader expression. Retained as non-core.
- term:
    id: GO:0060047
    label: heart contraction
  evidence_type: IMP
  original_reference_id: PMID:25866181
  review:
    summary: >-
      IMP annotation for heart contraction based on Buhrdel et al. 2015
      (PMID:25866181). Morpholino knockdown of MFM genes including cryaba led to
      severe heart failure in zebrafish. This reflects the broader role of sHSPs
      in muscle maintenance.
    action: KEEP_AS_NON_CORE
    reason: >-
      The heart failure phenotype from cryaba knockdown (PMID:25866181) supports
      involvement in cardiac function. However, zebrafish cryaba is predominantly
      lens-specific (PMID:16420472), making cardiac function a secondary role.
      Retained as non-core.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:18406404
  review:
    summary: >-
      IDA annotation for plasma membrane localization based on Cassidy-Hanley et al.
      2008 (PMID:18406404). The study on lengsin expression in zebrafish lens showed
      that alphaB1-crystallin (cryaba) localizes around the entire fiber cell membrane,
      producing a honeycomb appearance in cross-sectional profiles of adult lens tissue.
      This membrane-associated localization pattern is distinct from the cytoplasmic
      localization typical of sHSPs and may reflect a lens-specific structural role.
    action: ACCEPT
    reason: >-
      Direct experimental evidence from immunofluorescence in zebrafish lens
      (PMID:18406404) demonstrates that cryaba localizes to the plasma membrane of
      lens fiber cells. This is a valid localization annotation, though the membrane
      association may reflect a lens-specific structural role rather than a general
      property of the protein. This is consistent with the structural constituent of
      eye lens function.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:15692462
  review:
    summary: >-
      IDA annotation based on Dahlman et al. 2005 (PMID:15692462), which compared
      chaperone-like activity of zebrafish and mammalian alpha-crystallins. Zebrafish
      alphaB-crystallin (cryaba) showed reduced chaperone-like activity compared to
      mammalian CRYAB and to zebrafish cryaa. GO:0051082 is proposed for obsoletion.
      The holdase function demonstrated should be captured by GO:0140309.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. The chaperone-like activity assays in
      PMID:15692462 demonstrate reduced but measurable holdase function for cryaba.
      GO:0140309 (unfolded protein carrier activity) is the recommended replacement
      term for holdase chaperones.
    proposed_replacement_terms:
      - id: GO:0051082
        label: unfolded protein binding (retain until holdase NTR is created)
    supported_by:
      - reference_id: PMID:15692462
        supporting_text: >-
          The chaperone-like activities of the two zebrafish alpha-crystallins were
          highly divergent, with alphaA-crystallin showing much greater activity than
          alphaB-crystallin.
      - reference_id: PMID:15692462
        supporting_text: >-
          The reduced chaperone-like function of zebrafish alphaB-crystallin and its
          lack of extralenticular expression indicates that it plays a different
          physiological role from its mammalian ortholog.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15692462
  title: 'Zebrafish alpha-crystallins: protein structure and chaperone-like activity
    compared to their mammalian orthologs.'
  findings:
    - statement: >-
        Zebrafish alphaB-crystallin (cryaba) has reduced chaperone-like activity
        compared to zebrafish alphaA-crystallin and mammalian orthologs.
      supporting_text: >-
        The chaperone-like activities of the two zebrafish alpha-crystallins were
        highly divergent, with alphaA-crystallin showing much greater activity than
        alphaB-crystallin.
- id: PMID:16420472
  title: Gene duplication and separation of functions in alphaB-crystallin from zebrafish
    (Danio rerio).
  findings:
    - statement: >-
        Zebrafish express two alphaB-crystallins after gene duplication. cryaba
        (alphaB1) is predominantly lens-specific while cryabb (alphaB2) retains
        broad expression similar to mammalian CRYAB. cryaba makes up approximately
        0.16% of total lens protein and has reduced chaperone-like activity
        compared to cryabb and human CRYAB.
      supporting_text: >-
        zebrafish alphaB2 maintained the widespread protective role also found in
        mammalian alphaB-crystallin, while zebrafish alphaB1 adopted a more
        restricted, nonchaperone role in the lens.
- id: PMID:18406404
  title: Lengsin expression and function during zebrafish lens formation.
  findings:
    - statement: >-
        alphaB1-crystallin (cryaba) localizes around the entire fiber cell membrane
        in zebrafish lens, producing a honeycomb appearance in cross-sectional
        profiles.
- id: PMID:25866181
  title: In vivo characterization of human myofibrillar myopathy genes in zebrafish.
  findings:
    - statement: >-
        Morpholino knockdown of myofibrillar myopathy genes including cryaba in
        zebrafish led to compromised skeletal muscle function, myofibrillar
        degeneration, and severe heart failure.
      supporting_text: >-
        targeted ablation of MFM genes in zebrafish led to compromised skeletal
        muscle function mostly due to myofibrillar degeneration as well as severe
        heart failure.
- id: PMID:38705506
  title: "Loss of \u03B1Ba-crystallin, but not \u03B1A-crystallin, increases age-related\
    \ cataract in the zebrafish lens."
  findings:
    - statement: >-
        Loss of cryaba increases age-related cataract in zebrafish more than loss
        of cryaa. An ontogenetic shift occurs from cryaa predominance at 5-6 dpf
        to increased cryaba importance after 10 dpf.
      supporting_text: >-
        we found that the loss of the alphaBa-crystallin gene cryaba led to an
        increase in lens opacity compared to cryaa null fish at 24 months of age.
core_functions:
  - molecular_function:
      id: GO:0005212
      label: structural constituent of eye lens
    directly_involved_in:
      - id: GO:0036438
        label: maintenance of lens transparency
    locations:
      - id: GO:0005737
        label: cytoplasm
      - id: GO:0005886
        label: plasma membrane
    description: >-
      cryaba is a predominantly lens-specific alpha-crystallin that serves as a
      structural protein in zebrafish lens fiber cells. It localizes around the
      entire fiber cell membrane (PMID:18406404) and its loss leads to increased
      age-related cataract (PMID:38705506). cryaba plays a leading role in
      preventing age-related cataract, with an ontogenetic shift from cryaa
      predominance in early development to cryaba importance during lens aging
      (PMID:38705506).
  - molecular_function:
      id: GO:0051082
      label: unfolded protein binding
    directly_involved_in:
      - id: GO:0009408
        label: response to heat
    locations:
      - id: GO:0005737
        label: cytoplasm
    description: >-
      cryaba retains some holdase chaperone activity, though reduced compared to
      zebrafish cryaa and mammalian CRYAB (PMID:15692462, PMID:16420472). After
      gene duplication, cryaba adopted a more restricted, nonchaperone role in the
      lens while cryabb maintained the widespread protective role of mammalian
      CRYAB (PMID:16420472). The chaperone activity of cryaba is a secondary
      function.