NID1

id: P14543
gene_symbol: NID1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Nidogen-1 (also called entactin) is a critical basement membrane glycoprotein
  that functions as an architectural linker protein bridging the laminin and collagen
  IV networks. The 1247 amino acid protein contains three globular domains (G1, G2,
  G3) connected by rod-like segments with EGF-like repeats. The G2 domain binds with
  high affinity to the laminin gamma-1 chain, while the G3 domain binds collagen IV.
  Nidogen-1 also binds perlecan and fibulins, serving as a central organizing element
  in basement membrane assembly. This bridging function is essential for basement membrane
  structural integrity across diverse tissues including skin, muscle, and nervous system.
  The protein is ubiquitously expressed in basement membranes throughout the body and
  represents one of the core structural constituents of the basement membrane extracellular
  matrix.
existing_annotations:
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Nidogen-1 contains multiple calcium-binding EGF-like domains in its central
      rod region, as indicated by InterPro domain annotations. UniProt features annotate
      calcium-binding EGF-like domains at positions 710-751 and 802-840.
    action: ACCEPT
    reason: This is a legitimate molecular function supported by domain architecture.
      Nidogen-1 contains calcium-binding EGF-like repeats in the rod domain connecting
      G2 and G3 globules, as confirmed by InterPro annotations and UniProt features.
      PMID:2119632 notes "The molecule binds calcium ions" as one of nidogen's properties.
      While not the core bridging function, calcium binding may play a role in maintaining
      structural integrity.
    supported_by:
    - reference_id: GO_REF:0000002
      supporting_text: InterPro domain IPR001881 (EGF-like calcium-binding domain)
        and IPR018097 (EGF calcium-binding domain conserved site) mapped to NID1
    - reference_id: PMID:2119632
      supporting_text: The molecule binds calcium ions and supports cell adhesion.
        However, its major function may be the assembly of the basement membrane.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Nidogen-1 is a secreted protein localized to the extracellular space,
      specifically in basement membranes. This is an accurate but overly general localization
      term.
    action: ACCEPT
    reason: This annotation is correct but the more specific terms basement membrane
      (GO:0005604) and extracellular matrix (GO:0031012) are preferable. However,
      as a parent term this remains valid and useful for broad queries. UniProt clearly
      states secreted extracellular space location.
    supported_by:
    - reference_id: GO_REF:0000117
      supporting_text: ARBA machine learning model prediction based on sequence features
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Nidogen-1 is a ubiquitous and integral component of basement membranes.
      This is THE primary localization for this protein.
    action: ACCEPT
    reason: This is absolutely correct and represents the core localization of nidogen-1.
      Basement membrane localization is fundamental to nidogen-1's function as a structural
      linker. UniProt annotation explicitly states "Secreted, extracellular space,
      extracellular matrix, basement membrane" and emphasizes nidogen-1 is "widely
      distributed in basement membranes."
    supported_by:
    - reference_id: GO_REF:0000120
      supporting_text: Combined automated annotation methods including orthology to
        mouse UniProtKB:P10493 and SubCell localization SL-0025 (basement membrane)
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Cell adhesion is a consequence of basement membrane organization and ECM
      structural function. This is a plausible but indirect annotation.
    action: KEEP_AS_NON_CORE
    reason: While nidogen-1 supports cell adhesion indirectly by organizing the basement
      membrane ECM to which cells adhere, this is not its direct molecular function.
      PMID:2119632 mentions "supports cell adhesion" and PMID:3794389 examines "Effect
      of basement membrane entactin on epidermal cell attachment and growth," but
      the primary function is ECM structural organization. The cell adhesion effects
      are secondary to the structural role. This annotation is acceptable but represents
      a downstream consequence rather than core function.
    supported_by:
    - reference_id: GO_REF:0000043
      supporting_text: Based on UniProtKB keyword KW-0130 (Cell adhesion)
    - reference_id: PMID:2119632
      supporting_text: The molecule binds calcium ions and supports cell adhesion.
        However, its major function may be the assembly of the basement membrane.
- term:
    id: GO:0007160
    label: cell-matrix adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Cell-matrix adhesion is supported by nidogen-1's role in organizing the
      basement membrane matrix that mediates cell-ECM interactions.
    action: KEEP_AS_NON_CORE
    reason: Similar to cell adhesion (GO:0007155), this represents a consequence of
      nidogen-1's structural role rather than its direct function. The InterPro NIDO
      domain (IPR003886) is associated with cell-matrix interactions, but nidogen-1's
      primary role is as a structural bridge between laminin and collagen IV networks.
      Cell-matrix adhesion is mediated by the organized basement membrane that nidogen-1
      helps assemble. Keep as non-core.
    supported_by:
    - reference_id: GO_REF:0000002
      supporting_text: InterPro domain IPR003886 (NIDO domain) mapped to process involved
        in cell-matrix adhesion
- term:
    id: GO:0043236
    label: laminin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Laminin binding via the G2 domain is one of THE core molecular functions
      of nidogen-1. High-affinity binding to laminin gamma-1 chain is critical for
      basement membrane assembly.
    action: ACCEPT
    reason: This is absolutely a core molecular function. The G2 domain of nidogen-1
      binds with high affinity to the laminin gamma-1 chain. PMID:22952693 extensively
      characterizes nidogen-1 binding to laminin and shows cathepsin S cleavage impairs
      this interaction. PMID:23948589 structural study confirms "the interaction is
      mediated solely by the C-terminal domains" for laminin-nidogen complex. UniProt
      function states nidogen-1 is "tightly associated with laminin." This is essential
      for the bridging function.
    supported_by:
    - reference_id: GO_REF:0000117
      supporting_text: ARBA machine learning model ARBA00086571 predicting laminin
        binding
    - reference_id: PMID:22952693
      supporting_text: Nid-1 was cleaved within its G2 and G3 globular domains that
        are both involved in interactions with other BM components. Binding assays
        with soluble and immobilized ligands indicated that catS altered the formation
        of complexes between nid-1 and other BM components.
    - reference_id: PMID:23948589
      supporting_text: The ab initio shape reconstruction of the complex between nidogen-1
        and the laminin gamma-1 short arm confirms that the interaction is mediated
        solely by the C-terminal domains
- term:
    id: GO:0071711
    label: basement membrane organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Basement membrane organization is THE core biological process for nidogen-1.
      It serves as the central organizing element linking laminin and collagen IV
      networks.
    action: ACCEPT
    reason: This is the primary biological process annotation for nidogen-1. PMID:2119632
      states "its major function may be the assembly of the basement membrane" and
      describes nidogen as serving "as a bridge between the two most abundant molecules
      in the basement membrane." PMID:22952693 describes nidogens as playing "a central
      role in the supramolecular organization of the basal laminae in tissues such
      as skin, muscle, lung and the nervous system." This is THE defining function
      of nidogen-1.
    supported_by:
    - reference_id: GO_REF:0000117
      supporting_text: ARBA machine learning model ARBA00085295 predicting basement
        membrane organization
    - reference_id: PMID:2119632
      supporting_text: However, its major function may be the assembly of the basement
        membrane.
    - reference_id: PMID:22952693
      supporting_text: Both nidogens play a central role in the supramolecular organization
        of the basal laminae in tissues such as skin, muscle, lung and the nervous
        system
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Collagen IV binding via the G3 domain is one of THE core molecular functions
      of nidogen-1, essential for bridging laminin to collagen IV networks.
    action: ACCEPT
    reason: This is absolutely a core molecular function. The G3 domain binds collagen
      IV. PMID:2119632 states "This same region is also believed to be responsible
      for the attachment of entactin to type IV collagen at approximately 80 nm from
      its carboxyl noncollagenous end." PMID:22952693 demonstrates cathepsin cleavage
      within G3 impairs collagen binding. UniProt function notes nidogen "Also binds
      to collagen IV." This collagen IV binding is the other half of nidogen-1's critical
      bridging function.
    supported_by:
    - reference_id: GO_REF:0000120
      supporting_text: Automated annotation based on orthology to mouse (UniProtKB:P10493,
        ensembl:ENSMUSP00000005532) with combined evidence
    - reference_id: PMID:2119632
      supporting_text: Entactin therefore could serve as a bridge between the two
        most abundant molecules in the basement membrane.
    - reference_id: PMID:22952693
      supporting_text: "Cleavage sites were identified within G2 and G3 globular domains that are both involved in interactions with other BM components (type IV collagen, laminin, perlecan)"
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Nidogen-1 is an integral structural component of the extracellular matrix,
      specifically the basement membrane ECM.
    action: ACCEPT
    reason: This is accurate and appropriate. Basement membrane (GO:0005604) is a
      child term of extracellular matrix (GO:0031012), so this parent term is valid.
      Nidogen-1 is one of the major ECM proteins. UniProt emphasizes ECM localization,
      and PMID:22952693 describes nidogen's role in "extracellular matrix (ECM)" turnover
      and organization. This is a good general ECM annotation.
    supported_by:
    - reference_id: GO_REF:0000107
      supporting_text: Ensembl automatic transfer from ortholog mouse UniProtKB:P10493
        (ensembl:ENSMUSP00000005532)
    - reference_id: PMID:22952693
      supporting_text: Both nidogens play a central role in the supramolecular organization
        of the basal laminae in tissues such as skin, muscle, lung and the nervous
        system
- term:
    id: GO:0043237
    label: laminin-1 binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Laminin-1 (laminin-111, alpha1beta1gamma1) binding is a specific instance
      of nidogen-1's laminin binding activity. The binding is to the gamma-1 chain
      shared across multiple laminin isoforms.
    action: ACCEPT
    reason: This is a more specific child term of laminin binding (GO:0043236). Nidogen-1
      binds to the gamma-1 chain of laminins, including laminin-1 (laminin-111). PMID:22952693
      notes that nidogen-1 "is more resistant to degradation when complexed with laminin-111
      (alpha1beta1gamma1) (the binding site for nidogens locates in gamma 1 chain)."
      Since the binding site is on the gamma-1 chain, nidogen-1 can bind various laminins
      containing gamma-1. This specific annotation to laminin-1 is valid.
    supported_by:
    - reference_id: GO_REF:0000107
      supporting_text: Ensembl automatic transfer from ortholog mouse UniProtKB:P10493
    - reference_id: PMID:22952693
      supporting_text: "Isolated nid-1 is readily hydrolyzed by serine proteases and metalloproteinases (MMPs) [9]–[13], however it is more resistant to degradation when complexed with laminin-111 (α1β1γ1) (the binding site for nidogens locates in gamma 1 chain) [14]"
- term:
    id: GO:0050840
    label: extracellular matrix binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Nidogen-1 binds multiple ECM components including laminin, collagen IV,
      and perlecan. This is a valid general ECM binding annotation.
    action: ACCEPT
    reason: This parent term appropriately captures nidogen-1's multiple ECM binding
      activities. It binds laminin (GO:0043236), collagen IV (GO:0005518), and perlecan
      (GO:0043394). PMID:22952693 describes nidogen-1 as having "several binding sites
      (localized to its G2 and G3 domains) for other BM components." UniProt states
      it "Also binds to collagen IV and perlecan." This general ECM binding term is
      appropriate given the multiple specific binding partners.
    supported_by:
    - reference_id: GO_REF:0000107
      supporting_text: Ensembl automatic transfer from ortholog mouse UniProtKB:P10493
    - reference_id: PMID:22952693
      supporting_text: Though nid-1 cannot self-assemble, unlike most ECM molecules,
        it has several binding sites (localized to its G2 and G3 domains) for other
        BM components.
- term:
    id: GO:0071944
    label: cell periphery
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cell periphery is an overly general and imprecise localization for nidogen-1,
      which is specifically secreted into the extracellular space.
    action: REMOVE
    reason: This annotation is misleading. GO:0071944 (cell periphery) includes both
      plasma membrane and cell wall, which are not appropriate for nidogen-1. Nidogen-1
      is a secreted protein that localizes to the extracellular basement membrane,
      not to cellular membranes or cell periphery structures. While the basement membrane
      is adjacent to cells, "cell periphery" suggests association with the cell surface
      itself rather than the extracellular space. The more specific terms basement
      membrane (GO:0005604) and extracellular matrix (GO:0031012) are far more appropriate.
      This appears to be an overly broad IEA annotation that should be removed.
    supported_by:
    - reference_id: GO_REF:0000107
      supporting_text: Ensembl automatic transfer from ortholog, but the annotation
        is not appropriate for a secreted ECM protein
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:23658023
  review:
    summary: High-throughput detection of nidogen-1 in ECM preparations from human
      embryonic stem cell cultures. Confirms ECM localization.
    action: ACCEPT
    reason: This HDA (high-throughput direct assay) evidence from proteomics confirms
      nidogen-1 presence in purified extracellular matrix samples. PMID:23658023 title
      is "Comparative proteomic analysis of supportive and unsupportive extracellular
      matrix substrates for human embryonic stem cell maintenance." Detection of nidogen-1
      in ECM preparations validates its ECM localization. This complements other ECM
      annotations with experimental proteomics data.
    supported_by:
    - reference_id: PMID:23658023
      supporting_text: Comparative proteomic analysis of supportive and unsupportive
        extracellular matrix substrates for human embryonic stem cell maintenance
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: NAS
  original_reference_id: PMID:1678389
  review:
    summary: Study on cross-linking of laminin-nidogen complexes by transglutaminase
      for basement membrane stabilization. Confirms basement membrane localization.
    action: ACCEPT
    reason: PMID:1678389 title is "Cross-linking of laminin-nidogen complexes by tissue
      transglutaminase. A novel mechanism for basement membrane stabilization." This
      NAS (non-traceable author statement) annotation is from ComplexPortal curation
      based on published literature describing nidogen-1 in basement membrane context.
      The annotation is well-supported and basement membrane is THE primary localization
      for nidogen-1.
    supported_by:
    - reference_id: PMID:1678389
      supporting_text: Cross-linking of laminin-nidogen complexes by tissue transglutaminase
- term:
    id: GO:0045785
    label: positive regulation of cell adhesion
  evidence_type: NAS
  original_reference_id: PMID:3794389
  review:
    summary: Study examining entactin effects on epidermal cell attachment and growth.
      This represents indirect downstream effects of ECM organization.
    action: KEEP_AS_NON_CORE
    reason: PMID:3794389 title is "Effect of basement membrane entactin on epidermal
      cell attachment and growth." While nidogen-1 does enhance cell adhesion by organizing
      the basement membrane substrate, this is a regulatory/downstream effect rather
      than its direct core function. The annotation is from ComplexPortal NAS curation.
      Similar to GO:0007155 (cell adhesion), this represents a consequence of nidogen-1's
      structural organizing role. Keep as non-core function.
    supported_by:
    - reference_id: PMID:3794389
      supporting_text: Effect of basement membrane entactin on epidermal cell attachment
        and growth
- term:
    id: GO:0051149
    label: positive regulation of muscle cell differentiation
  evidence_type: NAS
  original_reference_id: PMID:26555376
  review:
    summary: Study showing laminin and entactin enhance impaired myotube formation
      on collagen. This is a tissue-specific developmental effect.
    action: KEEP_AS_NON_CORE
    reason: PMID:26555376 title is "Impaired primary mouse myotube formation on crosslinked
      type I collagen films is enhanced by laminin and entactin." This describes a
      specific role in muscle cell differentiation, which is a specialized context-dependent
      function. While valid, this represents a developmental/tissue-specific process
      rather than nidogen-1's core structural bridging function. ComplexPortal NAS
      annotation. This is peripheral to core function - keep as non-core.
    supported_by:
    - reference_id: PMID:26555376
      supporting_text: Impaired primary mouse myotube formation on crosslinked type
        I collagen films is enhanced by laminin and entactin.
- term:
    id: GO:0098637
    label: protein complex involved in cell-matrix adhesion
  evidence_type: NAS
  original_reference_id: PMID:3109910
  review:
    summary: Study on laminin-nidogen complex extraction and structural characterization.
      Nidogen-1 is part of complexes mediating cell-matrix interactions.
    action: ACCEPT
    reason: PMID:3109910 title is "Laminin-nidogen complex. Extraction with chelating
      agents and structural characterization." This ComplexPortal NAS annotation describes
      nidogen-1 as part of the laminin-nidogen complex that mediates cell-matrix adhesion.
      While cell adhesion is downstream of the structural role, the complex itself
      is a valid annotation. The laminin-nidogen complex is a well-characterized structural
      unit that does mediate cell-ECM interactions. Accept as valid complex annotation.
    supported_by:
    - reference_id: PMID:3109910
      supporting_text: Large quantities of intact laminin-nidogen complex could be
        extracted from a mouse tumor basement membrane with a physiological buffer
        containing EDTA.
- term:
    id: GO:0110011
    label: regulation of basement membrane organization
  evidence_type: NAS
  original_reference_id: PMID:2119632
  review:
    summary: Classic review on entactin structure and function emphasizing basement
      membrane assembly role. Core regulatory function.
    action: ACCEPT
    reason: PMID:2119632 is the key review "Entactin structure and function" that
      established nidogen-1's role in basement membrane assembly. States "its major
      function may be the assembly of the basement membrane" and "Entactin therefore
      could serve as a bridge between the two most abundant molecules in the basement
      membrane." This is THE central function of nidogen-1 - regulating/organizing
      basement membrane structure. ComplexPortal NAS curation is well-supported. This
      is core function.
    supported_by:
    - reference_id: PMID:2119632
      supporting_text: However, its major function may be the assembly of the basement
        membrane.
- term:
    id: GO:2001046
    label: positive regulation of integrin-mediated signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:23948589
  review:
    summary: Structural study of full-length nidogen and laminin-nidogen complex.
      The annotation about integrin signaling is inferential.
    action: KEEP_AS_NON_CORE
    reason: PMID:23948589 is the structural study "Structural elucidation of full-length
      nidogen and the laminin-nidogen complex in solution." While this paper characterizes
      the structure, the connection to integrin-mediated signaling is indirect - the
      organized basement membrane containing laminin-nidogen complexes provides a substrate
      for integrin binding and signaling. This is a downstream regulatory effect rather
      than direct function. ComplexPortal NAS annotation infers signaling effects.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:23948589
      supporting_text: Nidogen-1 is a key basement membrane protein that is required
        for many biological activities.
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:28675934
  review:
    summary: Nidogen-1 is an integral structural component of basement membrane ECM.
      This is THE core molecular function.
    action: ACCEPT
    reason: Extracellular matrix structural constituent (GO:0005201) perfectly captures
      nidogen-1's core function as a structural bridging protein in basement membranes.
      Multiple RCA (inferred from reviewed computational analysis) annotations from
      ECM proteomics studies all support this function. This is the most appropriate
      molecular function term for nidogen-1.
    supported_by:
    - reference_id: PMID:28675934
      supporting_text: The extracellular matrix (ECM) is a complex meshwork of insoluble fibrillar proteins
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28675934
  review:
    summary: Proteomics detection of nidogen-1 in ECM preparations.
    action: ACCEPT
    reason: HDA evidence from proteomics confirming ECM localization. Accept as valid.
    supported_by:
    - reference_id: PMID:28675934
      supporting_text: Characterization of the Extracellular Matrix of Normal and
        Diseased Tissues Using Proteomics.
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:27068509
  review:
    summary: ECM structural constituent annotation from varicose vein ECM proteomics.
    action: ACCEPT
    reason: RCA evidence from ECM proteomics. This is core function. Accept.
    supported_by:
    - reference_id: PMID:27068509
      supporting_text: "The proteomics analysis revealed the presence of >150 extracellular matrix proteins, of which 48 had not been previously detected in venous tissue"
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:27559042
  review:
    summary: ECM structural constituent from glycoproteomics study.
    action: ACCEPT
    reason: RCA evidence from ECM glycoproteomics. Core function. Accept.
    supported_by:
    - reference_id: PMID:27559042
      supporting_text: "RESULTS: ECM-related glycoproteins were identified in left and right atrial appendages from the same patients"
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to orthologs.
    action: ACCEPT
    reason: ISS (inferred from sequence or structural similarity) annotation transferring
      this core function from orthologs. This is appropriate for the conserved structural
      function. Accept.
    supported_by:
    - reference_id: GO_REF:0000024
      supporting_text: Manual transfer of experimentally verified GO annotation to
        orthologs by curator judgment
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:20551380
  review:
    summary: ECM structural constituent from aorta ECM proteomics.
    action: ACCEPT
    reason: RCA evidence from aortic ECM proteomics. Core function. Accept.
    supported_by:
    - reference_id: PMID:20551380
      supporting_text: Proteomics characterization of extracellular space components
        in the human aorta
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:25037231
  review:
    summary: ECM structural constituent from colon cancer metastasis ECM proteomics.
    action: ACCEPT
    reason: RCA evidence from cancer ECM proteomics. Core function. Accept.
    supported_by:
    - reference_id: PMID:25037231
      supporting_text: We have been able to identify consistent changes in the ECM of i) colon tumors as compared with normal colon ECM; ii) primary tumors as compared with metastases derived from them
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:25037231
  review:
    summary: ECM localization from cancer proteomics.
    action: ACCEPT
    reason: HDA proteomics evidence for ECM localization. Accept.
    supported_by:
    - reference_id: PMID:25037231
      supporting_text: The ECM protein signatures of metastatic primary colon carcinomas
        and metastases to liver defined in this study
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:27068509
  review:
    summary: ECM localization from varicose vein proteomics.
    action: ACCEPT
    reason: HDA proteomics evidence for ECM localization. Accept.
    supported_by:
    - reference_id: PMID:27068509
      supporting_text: Extracellular matrix proteins were enriched from venous tissues
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:27559042
  review:
    summary: ECM localization from glycoproteomics.
    action: ACCEPT
    reason: HDA proteomics evidence for ECM localization. Accept.
    supported_by:
    - reference_id: PMID:27559042
      supporting_text: Atrial specimens were analyzed by mass spectrometry after extraction
        of ECM proteins and enrichment for glycoproteins
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:20551380
  review:
    summary: ECM localization from aorta proteomics.
    action: ACCEPT
    reason: HDA proteomics evidence for ECM localization. Accept.
    supported_by:
    - reference_id: PMID:20551380
      supporting_text: Nidogen-1NID1_HUMAN136566415.0101
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: ISS
  original_reference_id: PMID:22261194
  review:
    summary: ECM localization inferred from similarity.
    action: ACCEPT
    reason: ISS annotation for ECM localization based on orthology. Accept.
    supported_by:
    - reference_id: PMID:22261194
      supporting_text: Proteomics analysis of cardiac extracellular matrix remodeling
        in a porcine model of ischemia/reperfusion injury
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  review:
    summary: Detection of nidogen-1 in extracellular exosomes from urine proteomics.
      Non-core peripheral localization.
    action: KEEP_AS_NON_CORE
    reason: While nidogen-1 can be detected in exosome preparations, this is not a
      primary or functional localization. Exosomes may contain basement membrane fragments
      or contamination from ECM. The core localization is basement membrane. Mark
      as non-core.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: In-depth proteomic analyses of exosomes isolated from expressed
        prostatic secretions in urine
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: IDA
  original_reference_id: PMID:22952693
  review:
    summary: Direct experimental evidence (IDA) for basement membrane localization
      from PMID:22952693 study.
    action: ACCEPT
    reason: This is IDA (inferred from direct assay) experimental evidence for THE
      core localization of nidogen-1. PMID:22952693 directly demonstrates nidogen-1
      in basement membranes. This is the gold standard evidence type. Absolutely accept.
    supported_by:
    - reference_id: PMID:22952693
      supporting_text: Cleavage of nidogen-1 by cathepsin S impairs its binding to
        basement membrane partners
- term:
    id: GO:0043394
    label: proteoglycan binding
  evidence_type: IPI
  original_reference_id: PMID:22952693
  review:
    summary: IPI experimental evidence showing nidogen-1 interacts with perlecan proteoglycan.
      Core binding function.
    action: ACCEPT
    reason: This is IPI (inferred from physical interaction) evidence specifically
      showing nidogen-1 binds proteoglycans including perlecan (UniProtKB:Q05793).
      Perlecan binding is part of nidogen-1's bridging function in basement membranes.
      UniProt states nidogen "Also binds to...perlecan." This is a core molecular
      function. Accept.
    supported_by:
    - reference_id: PMID:22952693
      supporting_text: "Cleavage sites were identified within G2 and G3 globular domains that are both involved in interactions with other BM components (type IV collagen, laminin, perlecan)"
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: IDA
  original_reference_id: PMID:22952693
  review:
    summary: IDA experimental evidence for collagen IV binding. THE core molecular
      function for bridging.
    action: ACCEPT
    reason: This is IDA (direct assay) experimental evidence for collagen binding,
      one of THE two essential binding activities (along with laminin binding) that
      define nidogen-1's bridging function. PMID:22952693 directly demonstrates collagen
      binding and shows cathepsin cleavage impairs it. This is absolutely core function.
      Accept.
    supported_by:
    - reference_id: PMID:22952693
      supporting_text: "Cleavage sites were identified within G2 and G3 globular domains that are both involved in interactions with other BM components (type IV collagen, laminin, perlecan)"
- term:
    id: GO:0043236
    label: laminin binding
  evidence_type: IDA
  original_reference_id: PMID:22952693
  review:
    summary: IDA experimental evidence for laminin binding. THE core molecular function
      for bridging.
    action: ACCEPT
    reason: This is IDA (direct assay) experimental evidence for laminin binding,
      one of THE two essential binding activities that define nidogen-1's bridging
      function. PMID:22952693 directly demonstrates laminin binding and shows cathepsin
      cleavage impairs it. This is absolutely core function. Accept.
    supported_by:
    - reference_id: PMID:22952693
      supporting_text: Cleavage sites were identified within G2 and G3 globular domains
        that are both involved in interactions with other BM components
- term:
    id: GO:0071711
    label: basement membrane organization
  evidence_type: TAS
  original_reference_id: PMID:22952693
  review:
    summary: TAS evidence for basement membrane organization. THE core biological
      process.
    action: ACCEPT
    reason: This is TAS (traceable author statement) evidence for THE defining biological
      process of nidogen-1. PMID:22952693 describes nidogen's central role in basement
      membrane supramolecular organization. This is the primary process annotation.
      Accept.
    supported_by:
    - reference_id: PMID:22952693
      supporting_text: Both nidogens play a central role in the supramolecular organization
        of the basal laminae in tissues
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  review:
    summary: Detection of nidogen-1 in urinary exosome proteomics. Non-core peripheral
      localization.
    action: KEEP_AS_NON_CORE
    reason: Duplicate of previous exosome annotation. While detected in exosome preparations,
      this is not a primary functional localization. Mark as non-core.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: Large-scale proteomics and phosphoproteomics of urinary
        exosomes
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3791319
  review:
    summary: Reactome pathway annotation for NID1 degradation by MMP19. Confirms extracellular
      localization.
    action: ACCEPT
    reason: Reactome TAS annotation based on pathway R-HSA-3791319 (NID1 degradation
      by MMP19). Confirms nidogen-1 is in extracellular space where it can be cleaved
      by secreted proteases. Accept as valid general localization.
    supported_by:
    - reference_id: Reactome:R-HSA-3791319
      supporting_text: Nidogen-1 (entactin) is a member of the nidogen family
        of basement membrane glycoproteins
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2426450
  review:
    summary: Reactome pathway annotation for Laminins-Nidogens binding collagen IV.
      Confirms extracellular localization.
    action: ACCEPT
    reason: Reactome TAS annotation based on pathway R-HSA-2426450 (Laminins:Nidogens
      binds collagen type IV networks). This pathway describes THE core function of
      nidogen-1 bridging laminin and collagen IV in the extracellular space. Accept
      as valid.
    supported_by:
    - reference_id: Reactome:R-HSA-2426450
      supporting_text: Laminin-bound nidogens can bind to type IV collagen (Aumailey et al. 1989,
        1993, Fox et al. 1991, Reinhardt et al. 1993, Ries et al. 2001, Bechtel et al. 2012)
core_functions:
- molecular_function:
    id: GO:0005201
    label: extracellular matrix structural constituent
  description: Nidogen-1 serves as a structural constituent of basement membrane extracellular
    matrix, providing architectural organization through its bridging function between
    laminin and collagen IV networks.
- molecular_function:
    id: GO:0043236
    label: laminin binding
  description: High-affinity binding to laminin gamma-1 chain via the G2 domain is
    one of the two essential molecular functions defining nidogen-1's basement membrane
    bridging role.
- molecular_function:
    id: GO:0005518
    label: collagen binding
  description: Binding to collagen IV via the G3 domain is the second essential molecular
    function, enabling nidogen-1 to bridge laminin networks to collagen IV networks
    in basement membranes.
- molecular_function:
    id: GO:0043394
    label: proteoglycan binding
  description: Binding to perlecan and other proteoglycans contributes to nidogen-1's
    role in organizing and stabilizing the basement membrane extracellular matrix.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms.
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity.
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara.
  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:1678389
  title: Cross-linking of laminin-nidogen complexes by tissue transglutaminase. A
    novel mechanism for basement membrane stabilization.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:20551380
  title: Proteomics characterization of extracellular space components in the human
    aorta.
  findings: []
- id: PMID:2119632
  title: 'Entactin: structure and function.'
  findings: []
- id: PMID:22261194
  title: Proteomics analysis of cardiac extracellular matrix remodeling in a porcine
    model of ischemia/reperfusion injury.
  findings: []
- id: PMID:22952693
  title: Cleavage of nidogen-1 by cathepsin S impairs its binding to basement membrane
    partners.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
- id: PMID:23658023
  title: Comparative proteomic analysis of supportive and unsupportive extracellular
    matrix substrates for human embryonic stem cell maintenance.
  findings: []
- id: PMID:23948589
  title: Structural elucidation of full-length nidogen and the laminin-nidogen complex
    in solution.
  findings: []
- id: PMID:25037231
  title: Extracellular matrix signatures of human primary metastatic colon cancers
    and their metastases to liver.
  findings: []
- id: PMID:26555376
  title: Impaired primary mouse myotube formation on crosslinked type I collagen films
    is enhanced by laminin and entactin.
  findings: []
- id: PMID:27068509
  title: 'Extracellular matrix remodelling in response to venous hypertension: proteomics
    of human varicose veins.'
  findings: []
- id: PMID:27559042
  title: Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in
    Human Atrial Fibrillation.
  findings: []
- id: PMID:28675934
  title: Characterization of the Extracellular Matrix of Normal and Diseased Tissues
    Using Proteomics.
  findings: []
- id: PMID:3109910
  title: Laminin-nidogen complex. Extraction with chelating agents and structural
    characterization.
  findings: []
- id: PMID:3794389
  title: Effect of basement membrane entactin on epidermal cell attachment and growth.
  findings: []
- id: Reactome:R-HSA-2426450
  title: Laminins:Nidogens binds collagen type IV networks
  findings: []
- id: Reactome:R-HSA-3791319
  title: NID1 degradation by MMP19
  findings: []