cryabb

id: A0A8M9Q8E3
gene_symbol: cryabb
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:7955
  label: Danio rerio
description: >-
  Zebrafish alpha-crystallin B chain b (cryabb, also known as cryab2 or
  alphaB2-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. Unlike cryaba which became lens-specific, cryabb retains
  the broad expression pattern of its mammalian ortholog CRYAB, with constitutive
  expression in heart, brain, skeletal muscle, liver, and lens (PMID:16420472). cryabb
  has greater chaperone-like activity than human CRYAB at 25-30 degrees C, while human
  CRYAB provides greater protection at 35-40 degrees C (PMID:16420472). cryabb
  maintained the widespread protective role found in mammalian CRYAB after gene
  duplication, while cryaba adopted a more restricted lens role (PMID:16420472).
  Morpholino knockdown of cryabb causes skeletal muscle defects, myofibril
  disassembly, heart failure, and locomotory impairment in zebrafish embryos
  (PMID:25866181). Loss of cryabb also contributes to maintenance of lens transparency
  (PMID:38705506), though its primary role appears to be in muscle and stress
  protection rather than lens structure. The protein belongs to the sHSP/HSP20 family
  with an alpha-crystallin domain and an N-terminal crystallin domain. UniProt
  annotates it with keywords for eye lens protein, metal-binding, and zinc.
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. cryabb
      retains the broad expression pattern and protective functions of mammalian
      CRYAB (PMID:16420472), making this inference more applicable than for the
      lens-specific cryaba paralog. However, anti-apoptosis is a downstream
      biological process rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Anti-apoptotic activity is a recognized function of the sHSP family and is
      more relevant for cryabb than cryaba given that cryabb retained the widespread
      protective role of mammalian CRYAB (PMID:16420472). However, this represents
      a downstream biological process rather than a core molecular function. Retained
      as non-core.
- 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. Consistent with the known biology of alpha-crystallins
      as cytoplasmic proteins.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established for alpha-crystallins and sHSPs.
      The IBA inference is phylogenetically sound and consistent with 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. cryabb belongs to the sHSP/HSP20 family and has
      robust chaperone-like activity (PMID:16420472), maintaining the widespread
      protective role of mammalian CRYAB. This is a well-supported annotation.
    action: ACCEPT
    reason: >-
      cryabb is a member of the sHSP family with demonstrated chaperone-like
      activity (PMID:16420472). It retained the broad protective function of
      mammalian CRYAB after gene duplication. Response to heat is a core function
      for this protein.
- 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.
      cryabb has robust chaperone-like (holdase) activity at physiological
      temperatures (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 cryabb. 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: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 sHSP orthologs. GO:0051082 is proposed for obsoletion. cryabb has
      demonstrated chaperone-like activity (PMID:16420472). The holdase function should
      be captured by GO:0140309.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. The holdase activity of cryabb has been
      demonstrated by in vitro chaperone assays showing robust prevention of substrate
      aggregation (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:0005198
    label: structural molecule activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation based on ARBA machine learning models. cryabb has the more
      specific annotation GO:0005212 (structural constituent of eye lens) from
      IEA, and its primary molecular function is holdase chaperone activity rather
      than a generic structural role. However, cryabb does have expression in the
      lens and the UniProt keyword KW-0273 (Eye lens protein) is annotated.
    action: ACCEPT
    reason: >-
      While GO:0005198 is general, it is not incorrect -- cryabb contributes to
      structural integrity in multiple tissues including lens and muscle. The more
      specific term GO:0005212 is also annotated. Acceptable as an IEA inference.
- 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). cryabb is expressed in the
      lens and contributes to lens transparency (PMID:38705506), though its primary
      role is in broad tissue protection rather than lens structure.
    action: KEEP_AS_NON_CORE
    reason: >-
      cryabb does contribute to lens transparency (PMID:38705506), but unlike cryaba,
      it retained the broad expression and protective function of mammalian CRYAB
      (PMID:16420472). The structural lens role is secondary to its widespread
      chaperone function. Retained as non-core.
- 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.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is well-established. This IEA annotation is consistent
      with the IBA annotation. Acceptable as automated confirmation.
- term:
    id: GO:0009892
    label: negative regulation of metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation based on ARBA machine learning models. This is a very broad
      biological process term. Alpha-crystallins can regulate metabolic processes
      through their chaperone activity, but GO:0009892 is too general to be
      informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0009892 (negative regulation of metabolic process) is excessively broad
      and uninformative. While sHSPs can influence metabolic processes indirectly
      through their chaperone activity, this IEA annotation does not capture any
      specific function of cryabb. The annotation likely reflects a generic ARBA
      prediction from sequence features shared by many proteins.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for negative regulation of apoptotic process based on ARBA
      machine learning models. Consistent with the IBA annotation for the same
      term and the known anti-apoptotic function of mammalian CRYAB.
    action: KEEP_AS_NON_CORE
    reason: >-
      This IEA annotation is consistent with the IBA annotation for the same term.
      The anti-apoptotic function is well-established for mammalian CRYAB and likely
      conserved in cryabb. However, this is a downstream biological process rather
      than a core molecular function. Retained as non-core consistent with the IBA.
- 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 has keywords for zinc and metal-binding based on ARBA evidence.
      While the annotation is technically correct, it is very general. The more
      specific term GO:0008270 (zinc ion binding) would be more informative.
    action: MODIFY
    reason: >-
      The annotation is too general. UniProt keywords indicate zinc binding for this
      protein. 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 examined individual mutant zebrafish lines for all
      three alpha-crystallin genes. While the primary finding was that cryaba loss led
      to the greatest increase in cataract, the study also evaluated cryabb mutants for
      lens transparency. cryabb contributes to lens maintenance but its primary role
      is in broad tissue protection.
    action: KEEP_AS_NON_CORE
    reason: >-
      The experimental evidence from PMID:38705506 supports a role for cryabb in lens
      transparency maintenance. However, cryabb's primary function is as a broadly
      expressed protective chaperone (PMID:16420472), and its lens role is secondary
      compared to cryaba. Retained as non-core.
    supported_by:
      - reference_id: PMID:38705506
        supporting_text: >-
          zebrafish express one lens-specific alphaA-crystallin gene (cryaa), they
          express two alphaB-crystallin genes, with one evolving lens specificity
          (cryaba) and the other retaining the broad expression of its mammalian
          ortholog (cryabb).
- 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). Morpholino knockdown of MFM disease genes including
      cryabb led to compromised skeletal muscle function due to myofibrillar
      degeneration. This is more relevant for cryabb than cryaba because cryabb
      retains the broad muscle expression of mammalian CRYAB (PMID:16420472).
    action: ACCEPT
    reason: >-
      cryabb retains the widespread expression including muscle tissue that is
      characteristic of mammalian CRYAB (PMID:16420472). The morpholino knockdown
      evidence (PMID:25866181) supports a direct role in skeletal muscle tissue
      development/maintenance. This is a core function for cryabb.
    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 cryabb led to compromised skeletal
      muscle function affecting locomotion.
    action: KEEP_AS_NON_CORE
    reason: >-
      The locomotory behavior phenotype from cryabb knockdown (PMID:25866181) is a
      downstream consequence of myofibrillar degeneration rather than a direct role
      in locomotion. Retained as non-core.
- 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 cryabb led to myofibrillar
      degeneration. This is consistent with the known role of mammalian CRYAB
      in maintaining myofibrillar integrity, and cryabb retains the broad
      muscle expression of its mammalian ortholog (PMID:16420472).
    action: ACCEPT
    reason: >-
      cryabb retains the broad muscle expression of mammalian CRYAB (PMID:16420472)
      and morpholino knockdown causes myofibrillar degeneration (PMID:25866181).
      Myofibril assembly/maintenance is a core function for cryabb, consistent
      with the known role of mammalian CRYAB as a major myofibrillar myopathy gene.
- 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 cryabb led to
      severe heart failure. cryabb retains the cardiac expression of mammalian CRYAB
      (PMID:16420472).
    action: ACCEPT
    reason: >-
      cryabb retains the broad expression including heart tissue characteristic of
      mammalian CRYAB (PMID:16420472). The heart failure phenotype from knockdown
      (PMID:25866181) supports a direct role in cardiac function. This is a core
      function for cryabb, consistent with human CRYAB being a cardiomyopathy gene.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:16420472
  review:
    summary: >-
      IDA annotation based on Smith et al. 2006 (PMID:16420472), which characterized
      the chaperone-like activity of alphaB2-crystallin (cryabb). The study measured
      the ability of recombinant cryabb to prevent chemically induced aggregation of
      alpha-lactalbumin and lysozyme at temperatures from 25 to 40 degrees C. cryabb
      showed greater chaperone-like activity than human CRYAB at 25-30 degrees C.
      GO:0051082 is proposed for obsoletion; the holdase function should be captured
      by GO:0140309.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. The chaperone-like activity assays in
      PMID:16420472 directly demonstrate holdase function for cryabb -- prevention
      of chemically induced aggregation of substrate proteins. GO:0140309 (unfolded
      protein carrier activity) is the recommended replacement term.
    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.
      - reference_id: PMID:16420472
        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.
- term:
    id: GO:0005575
    label: cellular_component
  evidence_type: ND
  original_reference_id: GO_REF:0000015
  review:
    summary: >-
      ND (no data) annotation indicating that no specific cellular component has been
      experimentally determined for cryabb. This is a placeholder annotation. However,
      IBA evidence supports cytoplasmic and nuclear localization, and IEA evidence
      supports cytoplasmic localization.
    action: ACCEPT
    reason: >-
      ND annotations are standard placeholders indicating no experimental data is
      available for a particular aspect. While there are IBA and IEA annotations for
      specific compartments, no direct experimental localization data exists for
      cryabb. This ND annotation is valid as a factual statement.
references:
- id: GO_REF:0000015
  title: Use of the ND evidence code for Gene Ontology (GO) terms
  findings: []
- 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:16420472
  title: Gene duplication and separation of functions in alphaB-crystallin from zebrafish
    (Danio rerio).
  findings:
    - statement: >-
        Zebrafish express two alphaB-crystallins. cryabb (alphaB2) has
        constitutive expression in heart, brain, skeletal muscle, liver, and lens,
        retaining the broad expression of mammalian CRYAB. cryabb shows greater
        chaperone-like activity than human CRYAB at 25-30 degrees C. After gene
        duplication, cryabb maintained the widespread protective role of mammalian
        CRYAB while cryaba adopted a lens-specific role.
      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:25866181
  title: In vivo characterization of human myofibrillar myopathy genes in zebrafish.
  findings:
    - statement: >-
        Morpholino knockdown of myofibrillar myopathy genes including cryabb 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: >-
        The study examined all three alpha-crystallin mutant zebrafish lines for
        age-related cataract. cryabb contributes to lens maintenance alongside
        cryaa and cryaba.
      supporting_text: >-
        zebrafish express one lens-specific alphaA-crystallin gene (cryaa), they
        express two alphaB-crystallin genes, with one evolving lens specificity
        (cryaba) and the other retaining the broad expression of its mammalian
        ortholog (cryabb).
core_functions:
  - molecular_function:
      id: GO:0051082
      label: unfolded protein binding
    directly_involved_in:
      - id: GO:0009408
        label: response to heat
      - id: GO:0030239
        label: myofibril assembly
      - id: GO:0007519
        label: skeletal muscle tissue development
      - id: GO:0060047
        label: heart contraction
    locations:
      - id: GO:0005737
        label: cytoplasm
    description: >-
      cryabb is the broadly expressed zebrafish alphaB-crystallin paralog that
      retained the widespread protective function of mammalian CRYAB after gene
      duplication (PMID:16420472). It has robust holdase chaperone activity,
      preventing aggregation of denaturing proteins at physiological temperatures
      (PMID:16420472). cryabb is expressed in heart, brain, skeletal muscle, liver,
      and lens. Its chaperone activity supports myofibrillar integrity and cardiac
      function, consistent with human CRYAB being a myofibrillar myopathy and
      cardiomyopathy gene (PMID:25866181).