E1BL04

id: E1BL04
gene_symbol: E1BL04
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9913
  label: Bos taurus
description: >-
  XIRP2 (Xin actin-binding repeat-containing protein 2, also known as CMYA3/cardiomyopathy-associated
  protein 3) is a large (3561 aa) actin-binding protein of the Xin family. It contains 26 Xin repeats
  that mediate F-actin binding and is expressed in striated muscle, particularly in cardiomyocytes at
  intercalated discs and in skeletal muscle at myotendinous junctions. XIRP2 localizes to the Z disc,
  cell-cell junctions, and focal adhesions, where it interacts with alpha-actinin and actin filaments to
  maintain sarcomeric integrity and regulate actin cytoskeleton organization. The protein plays roles in
  cardiac development and muscle maintenance, and variants in human XIRP2 have been associated with
  cardiomyopathy and sudden cardiac death.
existing_annotations:
- term:
    id: GO:0001725
    label: stress fiber
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: colocalizes_with
  review:
    summary: >-
      XIRP2 colocalizes with stress fibers based on phylogenetic inference from human (A4UGR9) and
      mouse (Q702N8) orthologs. Human XIRP2 has been shown to colocalize with stress fibers in
      non-muscle cell overexpression assays, consistent with its actin-binding activity mediated by
      Xin repeats. The qualifier colocalizes_with is appropriate as XIRP2 is not an integral
      component of stress fibers but rather associates with them.
    action: KEEP_AS_NON_CORE
    reason: >-
      Stress fiber colocalization is likely observed in experimental overexpression contexts rather
      than being a primary physiological localization for this muscle-specific protein. The core
      localizations are the Z disc and intercalated disc in cardiac and skeletal muscle.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: colocalizes_with
  review:
    summary: >-
      XIRP2 colocalizes with focal adhesions based on phylogenetic inference from human and mouse
      orthologs. In muscle cells, the analogous structures to focal adhesions are costameres and
      myotendinous junctions, where XIRP2 has been reported to localize. The colocalizes_with
      qualifier is appropriate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Focal adhesion colocalization is consistent with XIRP2 biology but represents a non-muscle
      cell context or the muscle-equivalent structure. The core localization is at the Z disc and
      intercalated disc.
- term:
    id: GO:0007015
    label: actin filament organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      XIRP2 is involved in actin filament organization based on phylogenetic inference from
      mouse Xirp2 (Q702N8). This is consistent with the protein's multiple Xin repeats that bind
      F-actin and its known role in maintaining sarcomeric actin architecture. Mouse Xirp2 knockout
      studies demonstrate disrupted actin organization in the heart.
    action: ACCEPT
    reason: >-
      Actin filament organization is a well-supported core biological process for XIRP2, given its
      domain architecture (26 Xin repeats binding F-actin) and the phenotypic consequences of
      loss-of-function in mouse.
- term:
    id: GO:0051015
    label: actin filament binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      XIRP2 binds actin filaments through its 26 Xin repeats, as supported by phylogenetic inference
      from both human (A4UGR9) and mouse (Q702N8) orthologs. The Xin repeat domain is a well-characterized
      actin-binding module, and the bovine protein contains the same domain architecture (18 Pfam Xin
      domains, 26 PROSITE Xin repeats). This is the most specific and informative molecular function
      annotation for the protein.
    action: ACCEPT
    reason: >-
      Actin filament binding is the core molecular function of XIRP2, directly mediated by its
      characteristic Xin repeat domains. This is more specific than the generic actin binding term.
    supported_by:
      - reference_id: file:BOVIN/E1BL04/E1BL04-uniprot.txt
        supporting_text: "Xin repeats bind F-actin"
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Actin binding is assigned via combined automated methods (InterPro IPR012510 Xin repeat and
      IPR030072 XIRP1/XIRP2 family). This is a parent term of the more specific GO:0051015 (actin
      filament binding) which is also annotated via IBA. Both are technically correct, but the more
      specific term is preferred.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0003779 (actin binding) is subsumed by the more specific GO:0051015 (actin filament binding)
      already present in the annotation set. The Xin repeats specifically bind F-actin (filamentous
      actin), making the filament-specific term more informative.
    supported_by:
      - reference_id: file:BOVIN/E1BL04/E1BL04-uniprot.txt
        supporting_text: "Xin repeats bind F-actin"
- term:
    id: GO:0030036
    label: actin cytoskeleton organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Actin cytoskeleton organization is assigned via InterPro domain mapping (IPR012510, IPR030072).
      This is a parent term of the more specific GO:0007015 (actin filament organization) already
      annotated via IBA. Both are correct, but the more specific term is preferred.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0030036 is a broader parent of GO:0007015 (actin filament organization) which is already
      annotated. The more specific term better captures XIRP2's role in organizing actin filaments
      within the sarcomere.
- term:
    id: GO:0030054
    label: cell junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Cell junction localization is assigned via InterPro (IPR012510). XIRP2 localizes to intercalated
      discs in cardiomyocytes, which are specialized cell junctions. The term is correct but very
      general; the more specific GO:0005911 (cell-cell junction) is also annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0030054 is a broad parent term. The more specific GO:0005911 (cell-cell junction) already
      present in the annotation set, and even more specific terms such as intercalated disc
      (GO:0014704) would better capture the known localization.
- term:
    id: GO:0070161
    label: anchoring junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Anchoring junction localization is assigned from UniProt subcellular location vocabulary mapping.
      The UniProt entry lists cell junction as the subcellular location. Intercalated discs contain
      adherens junctions (a type of anchoring junction), so this is biologically consistent with XIRP2
      localization at intercalated discs and myotendinous junctions.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation is consistent with XIRP2 biology. Intercalated discs contain adherens junctions
      (anchoring junctions), and XIRP2 is found at these structures. However, this is a broad
      localization term and not as informative as Z disc or intercalated disc.
- term:
    id: GO:0001725
    label: stress fiber
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: colocalizes_with
  review:
    summary: >-
      Duplicate of the IBA annotation above, transferred from human XIRP2 (A4UGR9) via Ensembl
      Compara orthology. The same biological reasoning applies: stress fiber colocalization is
      observed but not the primary physiological localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Redundant with the IBA annotation for the same term and qualifier. Stress fiber colocalization
      is not a core localization for this muscle-specific protein.
- term:
    id: GO:0005911
    label: cell-cell junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Cell-cell junction localization is transferred from mouse Xirp2 (Q4U4S6) via Ensembl Compara.
      XIRP2 localizes to intercalated discs, which are specialized cell-cell junctions in cardiac
      muscle. This is a reasonable annotation, though intercalated disc (GO:0014704) would be more
      precise.
    action: ACCEPT
    reason: >-
      XIRP2 is well-established at intercalated discs, which are specialized cell-cell junctions.
      This annotation correctly captures an important aspect of XIRP2 localization in cardiac tissue.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: colocalizes_with
  review:
    summary: >-
      Duplicate of the IBA annotation above, transferred from human XIRP2 (A4UGR9) via Ensembl
      Compara. Same reasoning applies as for the IBA version.
    action: KEEP_AS_NON_CORE
    reason: >-
      Redundant with the IBA annotation for the same term and qualifier. Focal adhesion
      colocalization represents a non-muscle context or the muscle-equivalent costamere.
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Z disc localization is transferred from mouse Xirp2 (Q4U4S6) via Ensembl Compara. XIRP2 is
      well-established as a Z disc component in striated muscle, where it interacts with alpha-actinin
      and maintains sarcomeric structure. This is one of the most important and well-characterized
      localizations for XIRP2.
    action: ACCEPT
    reason: >-
      Z disc localization is a core aspect of XIRP2 biology. The protein interacts with alpha-actinin
      at the Z disc and is essential for sarcomeric integrity in both cardiac and skeletal muscle.
- term:
    id: GO:0051015
    label: actin filament binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Duplicate of the IBA annotation above, transferred from human XIRP2 (A4UGR9) via Ensembl
      Compara. Same reasoning applies: actin filament binding is the core molecular function
      mediated by Xin repeats.
    action: ACCEPT
    reason: >-
      Actin filament binding is the defining molecular function of XIRP2. This Ensembl Compara
      annotation reinforces the IBA annotation from the same source ortholog.
    supported_by:
      - reference_id: file:BOVIN/E1BL04/E1BL04-uniprot.txt
        supporting_text: "Xin repeats bind F-actin"
- term:
    id: GO:0051393
    label: alpha-actinin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Alpha-actinin binding is transferred from mouse Xirp2 (Q4U4S6) via Ensembl Compara.
      XIRP2 has been shown to interact with alpha-actinin at the Z disc in mouse cardiomyocytes,
      which is important for its role in sarcomeric integrity. This interaction is distinct from
      and complementary to its actin filament binding activity.
    action: ACCEPT
    reason: >-
      Alpha-actinin binding is a well-characterized molecular function of XIRP2 that is important
      for its localization to the Z disc and its role in sarcomeric maintenance.
- term:
    id: GO:0110053
    label: regulation of actin filament organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Regulation of actin filament organization is transferred from mouse Xirp2 (Q4U4S6) via
      Ensembl Compara. This is consistent with XIRP2's role in maintaining sarcomeric actin
      architecture, though it is somewhat redundant with GO:0007015 (actin filament organization)
      already annotated via IBA.
    action: KEEP_AS_NON_CORE
    reason: >-
      While XIRP2 does regulate actin filament organization, the direct involvement in actin
      filament organization (GO:0007015) is a more fundamental annotation. The regulatory aspect
      is secondary to the structural role.
- term:
    id: GO:1903829
    label: positive regulation of protein localization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Positive regulation of protein localization is transferred from mouse Xirp2 (Q4U4S6) via
      Ensembl Compara. This is a very broad term. XIRP2 may promote the localization of specific
      proteins (such as alpha-actinin or other sarcomeric components) to the Z disc, but the term
      lacks specificity about which proteins or which localization context.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The term is too broad to be informative. Without specifying which protein's localization
      is being regulated, this annotation provides limited biological insight. A more specific
      term would be preferred if the regulated protein can be identified.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings:
    - statement: >-
        InterPro correctly identifies the Xin repeat domain (IPR012510) and the XIRP1/XIRP2 family
        (IPR030072), supporting actin binding and cell junction localization assignments.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
    - statement: >-
        IBA annotations transferred from human XIRP2 (A4UGR9) and mouse Xirp2 (Q702N8) are
        well-supported by phylogenetic conservation of the Xin repeat domain architecture and
        consistent functional characterization across mammalian orthologs.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings:
    - statement: >-
        UniProt subcellular location mapping correctly assigns cell junction and anchoring junction
        localization, consistent with XIRP2's known presence at intercalated discs and myotendinous
        junctions.
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
    using Ensembl Compara
  findings:
    - statement: >-
        Ensembl Compara transfers from human XIRP2 (A4UGR9) and mouse Xirp2 (Q4U4S6) provide
        the most informative annotations, including Z disc localization, alpha-actinin binding,
        and regulation of actin filament organization.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
    - statement: >-
        Combined IEA methods assign the general actin binding term, which is subsumed by the
        more specific actin filament binding term from IBA/Ensembl Compara.
- id: file:BOVIN/E1BL04/E1BL04-uniprot.txt
  title: UniProt entry E1BL04
  findings:
    - statement: >-
        UniProt identifies E1BL04 as XIRP2 with 26 PROSITE Xin repeats and 18 Pfam Xin domains,
        belonging to the Xin family. The protein is 3561 amino acids and localizes to cell junctions.
    - statement: >-
        Expression data from Bgee shows the gene is expressed in rectus femoris and 30 other
        cell types/tissues, consistent with striated muscle expression.
core_functions:
- description: >-
    XIRP2 binds F-actin filaments through its multiple Xin repeat domains (26 repeats),
    providing the molecular basis for its structural role at the Z disc and intercalated disc
    in striated muscle.
  molecular_function:
    id: GO:0051015
    label: actin filament binding
  locations:
    - id: GO:0030018
      label: Z disc
  directly_involved_in:
    - id: GO:0007015
      label: actin filament organization
  supported_by:
    - reference_id: file:BOVIN/E1BL04/E1BL04-uniprot.txt
      supporting_text: "Xin repeats bind F-actin"
- description: >-
    XIRP2 binds alpha-actinin at the Z disc, contributing to the structural integrity of
    the sarcomere and proper organization of the actin cytoskeleton in cardiac and skeletal
    muscle.
  molecular_function:
    id: GO:0051393
    label: alpha-actinin binding
  locations:
    - id: GO:0030018
      label: Z disc
  supported_by:
    - reference_id: file:BOVIN/E1BL04/E1BL04-uniprot.txt
      supporting_text: "Belongs to the Xin family"
suggested_questions:
  - question: >-
      Does bovine XIRP2 localize to the intercalated disc in cattle cardiomyocytes, as established
      for the human and mouse orthologs?
  - question: >-
      Are there cattle-specific variants in XIRP2 associated with bovine cardiomyopathy or sudden
      death, analogous to human XIRP2 variants linked to sudden cardiac death?
  - question: >-
      Does XIRP2 interact with other Z disc or intercalated disc components (e.g., beta-catenin,
      N-cadherin, p120-catenin) in bovine cardiac tissue?
suggested_experiments:
  - hypothesis: >-
      Bovine XIRP2 localizes to Z discs and intercalated discs in cattle cardiomyocytes, consistent
      with its mammalian orthologs.
    description: >-
      Perform immunofluorescence microscopy on bovine cardiac tissue sections using antibodies against
      XIRP2 and co-staining with alpha-actinin (Z disc marker) and N-cadherin (intercalated disc marker).
    experiment_type: immunofluorescence microscopy
  - hypothesis: >-
      The Xin repeat domains of bovine XIRP2 are sufficient for F-actin binding.
    description: >-
      Express recombinant bovine XIRP2 Xin repeat fragments and assay F-actin binding by cosedimentation
      or fluorescence anisotropy.
    experiment_type: protein-protein interaction assay