id: P17900
gene_symbol: GM2A
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GM2A (ganglioside GM2 activator protein; also called sphingolipid activator
  protein 3 / SAP-3 and cerebroside sulfate activator protein) is a small,
  soluble, non-catalytic lysosomal lipid-binding and lipid-transfer protein of
  the ML/GM2-AP family with a distinctive beta-cup fold. It is essential for the
  lysosomal degradation of ganglioside GM2: it extracts single GM2 molecules
  from the surface of intralysosomal luminal vesicles and presents them in
  soluble form to beta-hexosaminidase A (the HEXA/HEXB heterodimer), forming a
  stoichiometric GM2-GM2A complex that is the actual substrate for hydrolysis of
  the terminal N-acetylgalactosamine to yield GM3. GM2A is thus an obligatory
  cofactor of HexA rather than an enzyme itself, and it similarly assists
  breakdown of the related neutral glycolipid GA2. Its large hydrophobic binding
  pocket can accommodate other single-chain lipids (phospholipids, fatty acids)
  and it can participate in cholesterol transfer, and its lipid-mobilizing
  activity is modulated by the membrane lipid environment (inhibited by
  cholesterol, sphingomyelin, and sphingoid bases; stimulated by ceramide,
  anionic lipids such as BMP, fatty acids, and lysophosphatidylcholine). GM2A
  is synthesized with a cleaved signal peptide, N-glycosylated, and targeted to
  the lysosomal lumen, where it acts at the ILV membrane surface; it is also
  detectable in secreted/exosomal fractions. Loss of GM2A function causes the AB
  variant of GM2 gangliosidosis (a Tay-Sachs-like autosomal recessive lysosomal
  storage disease), in which GM2 accumulates in neurons despite normal
  hexosaminidase A and B activities.
existing_annotations:
- term:
    id: GO:0005319
    label: lipid carrier activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred lipid carrier activity. GM2A binds a specific
      lipid (GM2 ganglioside) and delivers it to an acceptor, matching the term
      definition. This is an accurate molecular function for GM2A.
    action: ACCEPT
    reason: >-
      GM2A directly binds single GM2 molecules and delivers/presents them to
      beta-hexosaminidase A, consistent with the lipid carrier activity
      definition ("binding to a specific lipid and delivering it either to an
      acceptor molecule or to a specific location"). Well supported by the
      curated UniProt function and the experimental literature.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Lipid-binding and transfer protein essential for lysosomal degradation
        of ganglioside GM2.
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement in ganglioside catabolism. This is
      the central biological process for GM2A, which is obligatory for lysosomal
      GM2 degradation.
    action: ACCEPT
    reason: >-
      GM2A is essential for the catabolism of ganglioside GM2 to GM3 by HexA.
      This is the core, disease-defining function (its loss causes GM2
      gangliosidosis AB variant). Correct and appropriately specific.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Lipid-binding and transfer protein essential for lysosomal degradation
        of ganglioside GM2.
- term:
    id: GO:0006869
    label: lipid transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred lipid transport. GM2A does mobilize and transfer
      lipids between membranes and acceptors, but its biological role is
      substrate mobilization/presentation within glycosphingolipid catabolism
      rather than bulk lipid transport.
    action: KEEP_AS_NON_CORE
    reason: >-
      The intramembrane/intermembrane transfer activity is real, but as a
      biological process for GM2A it is peripheral to (and captured better by)
      ganglioside catabolic process. Retain as non-core context.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Possesses dual function: membrane lipid mobilization/solubilization and
        lipid substrate presentation to hydrolases
- term:
    id: GO:0009898
    label: cytoplasmic side of plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred localization to the cytoplasmic side of the
      plasma membrane. This is inconsistent with GM2A biology: it is a soluble
      glycoprotein made with a cleaved signal peptide and targeted to the
      lysosomal lumen, with no cytosolic phase.
    action: REMOVE
    reason: >-
      GM2A carries an N-terminal signal peptide (residues 1-23), is
      N-glycosylated, and localizes to the lysosome (lumen)/ILV surface; it never
      faces the cytosol. Placement at the cytoplasmic side of the plasma membrane
      is a mislocalizing propagation and contradicts the topology of a secreted
      lysosomal protein.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location mapping to lysosome. This is the primary and
      correct site of GM2A function.
    action: ACCEPT
    reason: >-
      GM2A is a lysosomal protein; its function (GM2 mobilization and
      presentation to HexA) occurs in the lysosome. Consistent with the curated
      subcellular location.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO (IPR028996, GM2-AP domain) mapping to ganglioside catabolic
      process. Correct core biological process, redundant with the IBA/IDA
      annotations to the same term.
    action: ACCEPT
    reason: >-
      The GM2-AP family signature reliably predicts a role in ganglioside
      catabolism; agrees with the experimental and phylogenetic annotations.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Lipid-binding and transfer protein essential for lysosomal degradation
        of ganglioside GM2.
- term:
    id: GO:0008047
    label: enzyme activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Combined-IEA/ARBA mapping to enzyme activator activity. GM2A functionally
      activates beta-hexosaminidase A by presenting substrate, so the term is
      correct but generic; the more informative lipid chaperone / sphingolipid
      activator terms capture the mechanism.
    action: KEEP_AS_NON_CORE
    reason: >-
      GM2A is the obligatory cofactor that enables HexA to act on membrane-bound
      GM2, so enzyme activator activity is defensible, but it is a broad parent
      of the mechanistically precise lipid chaperone activity and sphingolipid
      activator protein activity terms. Keep as non-core.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Forms a stoichiometric GM2-GM2A complex that serves as the substrate for
        HEXA
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA mapping to glycosphingolipid catabolic process. GM2A assists
      degradation of glycosphingolipids (GM2 and the neutral glycolipid GA2), so
      this broader process is accurate.
    action: ACCEPT
    reason: >-
      GM2A participates in catabolism of glycosphingolipids beyond GM2 (e.g.
      stimulates GA2 breakdown by HexA); this parent process is correct and
      complements ganglioside catabolic process.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Also stimulates the breakdown of glycolipid GA2 by HEXA
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      High-throughput affinity-purification mass spectrometry (BioPlex 2.0)
      interaction, reported as generic protein binding with partner ACTA2
      (P62736). Uninformative and not the functional partner (HEXA).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is a proteome-scale AP-MS interactome dataset; the recorded partner
      (ACTA2, actin) is not a known functional partner of the lysosomal GM2A and
      the bare "protein binding" term conveys no specific function. Per curation
      policy, retained but flagged as over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: >-
        Architecture of the human interactome defines protein communities and
        disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS interaction (BioPlex 3.0), reported as generic
      protein binding with partner ACTA2 (P62736). As above, uninformative and
      not the functional HEXA partner.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same proteome-scale interactome pipeline as the BioPlex 2.0 record; the
      "protein binding" term is uninformative and the partner is not a validated
      functional interactor of GM2A. Retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: >-
        Dual proteome-scale networks reveal cell-specific remodeling of the
        human interactome.
- term:
    id: GO:0001573
    label: ganglioside metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara ortholog transfer (from rat) to ganglioside metabolic
      process. Correct but a broad parent of the more specific ganglioside
      catabolic process that GM2A performs.
    action: KEEP_AS_NON_CORE
    reason: >-
      GM2A acts specifically in ganglioside catabolism, a child of ganglioside
      metabolic process. The broader parent is not wrong but is less informative;
      keep as non-core.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Lipid-binding and transfer protein essential for lysosomal degradation
        of ganglioside GM2.
- term:
    id: GO:0005319
    label: lipid carrier activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl-Compara ortholog transfer of lipid carrier activity, redundant
      with the IBA annotation to the same term. Correct molecular function.
    action: ACCEPT
    reason: >-
      Duplicate of the accepted lipid carrier activity annotation; GM2A binds
      and delivers GM2 (and other lipids), matching the term.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Lipid-binding and transfer protein essential for lysosomal degradation
        of ganglioside GM2.
- term:
    id: GO:0006869
    label: lipid transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara ortholog transfer of lipid transport, redundant with the
      IBA annotation. As with the IBA record, real but peripheral relative to
      ganglioside catabolism.
    action: KEEP_AS_NON_CORE
    reason: >-
      GM2A mobilizes/transfers lipids, but its biological role is substrate
      mobilization within catabolism; retain lipid transport as non-core.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Possesses dual function: membrane lipid mobilization/solubilization and
        lipid substrate presentation to hydrolases
- term:
    id: GO:0009898
    label: cytoplasmic side of plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl-Compara ortholog transfer to the cytoplasmic side of the plasma
      membrane, duplicating the IBA record. Inconsistent with GM2A topology (a
      signal-peptide-bearing lumenal/secreted lysosomal glycoprotein).
    action: REMOVE
    reason: >-
      GM2A has no cytosolic phase; it is targeted to the lysosomal lumen via a
      cleaved signal peptide. The cytoplasmic-side-of-plasma-membrane placement
      is a mislocalizing propagation contradicted by the curated location.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0016004
    label: phospholipase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl-Compara ortholog transfer of phospholipase activator activity.
      GM2A itself has weak intrinsic (by-similarity) phospholipase activity but
      there is no evidence that it activates a distinct phospholipase enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The activator-of-phospholipase claim is not supported for human GM2A; the
      curated record notes only weak intrinsic calcium-independent phospholipase
      activity (by similarity), not activation of another phospholipase. Likely
      an over-propagated ortholog inference.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Exhibits some calcium-independent phospholipase activity
- term:
    id: GO:0016323
    label: basolateral plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl-Compara ortholog transfer (from rat) to basolateral plasma
      membrane. Reflects a possible surface/secretory pool of the rodent
      ortholog but is not the functional lysosomal site of GM2A.
    action: KEEP_AS_NON_CORE
    reason: >-
      GM2A is a secreted glycoprotein and may be detected at the cell surface,
      but its characterized function is lysosomal. Retain the plasma-membrane
      localization as non-core, not core.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl-Compara ortholog transfer to apical plasma membrane. As with the
      basolateral record, a possible surface pool but not the functional
      lysosomal site.
    action: KEEP_AS_NON_CORE
    reason: >-
      Non-core surface/secretory localization inferred from the rodent ortholog;
      GM2A's characterized activity is lysosomal.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0032428
    label: beta-N-acetylgalactosaminidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: >-
      Ensembl-Compara ortholog transfer assigning (contributes_to)
      beta-N-acetylgalactosaminidase activity. This is the catalytic activity of
      beta-hexosaminidase A (HEXA/HEXB), not of GM2A, which is non-catalytic.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GM2A does not hydrolyze the terminal N-acetylgalactosamine; it presents the
      GM2 substrate to HexA, which performs the cleavage. Assigning the
      glycosidase activity to the activator (even with contributes_to)
      over-attributes catalytic function to a non-enzymatic cofactor.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        presents them in soluble form to beta-hexosaminidase A (HEXA) for
        cleavage of N-acetyl-
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IDA
  original_reference_id: PMID:11707436
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental annotation to ganglioside catabolic process. This
      study reconstituted GM2A-assisted hydrolysis of membrane-bound
      sphingolipid substrate by hexosaminidase, supporting GM2A's catabolic role.
    action: ACCEPT
    reason: >-
      Experimental (IDA) support for GM2A's central catabolic role; the study
      shows GM2 activator protein synergistically stimulates hydrolysis of a
      membrane-bound glycosphingolipid substrate. Core biological process.
    supported_by:
    - reference_id: PMID:11707436
      supporting_text: >-
        Hydrolysis of membrane-bound SM2 by the recombinant Hex S was
        synergistically stimulated by the GM2 activator protein
- term:
    id: GO:0160317
    label: endolysosomal intralumenal vesicle membrane
  evidence_type: IC
  original_reference_id: PMID:11707436
  qualifier: is_active_in
  review:
    summary: >-
      Curator inference that GM2A is active at the endolysosomal intralumenal
      vesicle membrane, where it acts on membrane-bound glycosphingolipid
      substrates. Consistent with the mechanism of extracting lipids from ILVs.
    action: ACCEPT
    reason: >-
      GM2A functions at the ILV membrane surface, extracting single GM2/GA2
      molecules from intralysosomal luminal vesicles for presentation to HexA.
      This IC captures the precise site of action.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Extracts single GM2 molecules from intralysosomal luminal vesicle (ILV)
        membranes
- term:
    id: GO:7770043
    label: lipid chaperone activity
  evidence_type: IDA
  original_reference_id: PMID:11707436
  qualifier: enables
  review:
    summary: >-
      Direct experimental annotation to lipid chaperone activity. This precisely
      captures GM2A's mechanism: binding a lipid and delivering/presenting it to
      an acceptor protein (the enzyme HexA) for catalysis.
    action: ACCEPT
    reason: >-
      The lipid chaperone activity term ("binding to a lipid and delivering it to
      an acceptor protein... presented while bound to the chaperone for enzymatic
      modification") is the most mechanistically accurate MF for GM2A, which
      binds GM2 and presents it to HexA. This is the core molecular function.
    supported_by:
    - reference_id: PMID:11707436
      supporting_text: >-
        Hydrolysis of membrane-bound SM2 by the recombinant Hex S was
        synergistically stimulated by the GM2 activator protein
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Extracts single GM2 molecules from intralysosomal luminal vesicle (ILV)
        membranes
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840310
  qualifier: involved_in
  review:
    summary: >-
      Reactome pathway (Glycosphingolipid catabolism) annotation to
      glycosphingolipid catabolic process. Accurate for GM2A's role in
      degradation of GM2 and related glycosphingolipids.
    action: ACCEPT
    reason: >-
      GM2A participates in Reactome's glycosphingolipid catabolism, presenting
      glycosphingolipid substrates to hexosaminidases; the broad catabolic
      process is correct.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Also stimulates the breakdown of glycolipid GA2 by HEXA
- term:
    id: GO:0160317
    label: endolysosomal intralumenal vesicle membrane
  evidence_type: IC
  original_reference_id: PMID:27498570
  qualifier: is_active_in
  review:
    summary: >-
      Curator inference (based on GM2A's ganglioside catabolic role and the
      endolysosome as the site of acid hydrolase activity) that GM2A is active at
      the endolysosomal intralumenal vesicle membrane. Duplicate site annotation.
    action: ACCEPT
    reason: >-
      Endolysosomes are the principal sites of acid hydrolase activity, and GM2A
      acts at the ILV membrane there to mobilize substrate for HexA. Correct site
      of action; consistent with the other IC to the same term.
    supported_by:
    - reference_id: PMID:27498570
      supporting_text: >-
        Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase
        Activity
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Extracts single GM2 molecules from intralysosomal luminal vesicle (ILV)
        membranes
- term:
    id: GO:7770043
    label: lipid chaperone activity
  evidence_type: IDA
  original_reference_id: PMID:30988135
  qualifier: enables
  review:
    summary: >-
      Direct experimental annotation to lipid chaperone activity from a
      reconstitution study showing GM2A mobilizes/solubilizes membrane GM2 and
      presents it for hydrolysis, with the mobilization tracking hydrolysis. Core
      molecular function.
    action: ACCEPT
    reason: >-
      This study demonstrated that GM2A solubilizes/mobilizes membrane-bound GM2
      and that lipid mobilization by GM2A parallels its stimulation of GM2
      hydrolysis by HexA, directly supporting the lipid chaperone (bind-and-
      present) activity. Core MF, duplicate of the PMID:11707436 IDA.
    supported_by:
    - reference_id: PMID:30988135
      supporting_text: >-
        hydrolysis-inhibiting lipids also had an inhibiting effect on the
        solubilization and mobilization of membrane-bound lipids by the GM2
        activator protein
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IDA
  original_reference_id: PMID:30988135
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental annotation to ganglioside catabolic process from the
      reconstituted GM2 catabolism system. Core, disease-relevant biological
      process for GM2A.
    action: ACCEPT
    reason: >-
      The reconstitution of GM2 catabolism at liposomal surfaces with GM2A and
      HexA directly supports GM2A's role in ganglioside catabolism, including how
      membrane lipids modulate it. Core BP.
    supported_by:
    - reference_id: PMID:30988135
      supporting_text: >-
        incorporating lipids into the GM2-carrying membrane such as cholesterol,
        SM, sphingosine, and sphinganine inhibits GM2 hydrolysis by
        β-hexosaminidase A assisted by GM2 activator protein
- term:
    id: GO:0030290
    label: sphingolipid activator protein activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605717
  qualifier: enables
  review:
    summary: >-
      Reactome traceable annotation to sphingolipid activator protein activity,
      the family-level cofactor activity for lysosomal sphingolipid degradation.
      Accurate for GM2A (SAP-3).
    action: ACCEPT
    reason: >-
      GM2A is one of the sphingolipid activator proteins (SAP-3) that stimulate
      lysosomal enzymes degrading sphingolipids; the term correctly describes its
      cofactor activity, complementing the more precise lipid chaperone activity.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: >-
        Forms a stoichiometric GM2-GM2A complex that serves as the substrate for
        HEXA
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation (via neutrophil degranulation / exocytosis of
      azurophil granule lumen proteins) placing GM2A in the extracellular region.
      Reflects a secretory pool, not the primary functional site.
    action: KEEP_AS_NON_CORE
    reason: >-
      GM2A is a secreted glycoprotein and is exocytosed during neutrophil
      degranulation, so extracellular localization is defensible, but its
      characterized catabolic function is lysosomal. Retain as non-core.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to azurophil granule lumen, via the
      neutrophil-degranulation pathway. A secretory-granule localization, not the
      primary lysosomal functional site.
    action: KEEP_AS_NON_CORE
    reason: >-
      Azurophil (primary) granules are lysosome-related organelles of neutrophils
      and can contain GM2A; this is a legitimate but non-core localization
      relative to the classical lysosome where GM2A degrades GM2.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection of GM2A in extracellular exosomes
      (prostatic-secretion urinary exosomes). Consistent with a secreted/exosomal
      pool but not the functional lysosomal site.
    action: KEEP_AS_NON_CORE
    reason: >-
      Detection in exosome proteomes documents a secreted pool; exosomes derive
      from the endolysosomal/multivesicular-body system, so GM2A presence is
      plausible, but this is a localization observation rather than a functional
      site. Non-core.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: >-
        exosome preparations were characterized by a shotgun proteomics
        procedure
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection of GM2A in urinary exosomes. As above,
      a secreted/exosomal pool, non-core relative to its lysosomal function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Large-scale urinary-exosome proteomics detected GM2A; documents a secreted
      pool consistent with the endolysosomal origin of exosomes, but not the
      functional site. Non-core.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: >-
        we used LC-MS/MS to profile the proteome of human urinary exosomes
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605595
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to lysosomal lumen (bHEXA hydrolyzes
      GM2A-GM2 to GM2A-GM3). This is the primary, correct functional
      compartment for GM2A.
    action: ACCEPT
    reason: >-
      GM2A operates as a soluble activator in the lysosomal lumen, where it
      presents GM2 to HexA. The lysosomal-lumen localization is well established.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605624
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to lysosomal lumen (beta-galactosidases
      hydrolyse mobilized GM1 to mobilized GM2). Correct functional compartment;
      duplicate lysosomal-lumen localization.
    action: ACCEPT
    reason: >-
      Consistent, correct lysosomal-lumen localization for GM2A within the
      Reactome glycosphingolipid catabolism pathway.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605717
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to lysosomal lumen (GM2A binds and mobilizes
      ligands). Correct functional compartment; duplicate lysosomal-lumen
      localization.
    action: ACCEPT
    reason: >-
      GM2A binds and mobilizes its lipid ligands within the lysosomal lumen;
      correct localization consistent with the other lysosomal-lumen records.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840795
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to lysosomal lumen (beta-galactosidases
      hydrolyze GM2A-GA1 to GM2A-GA2). Correct functional compartment; duplicate
      lysosomal-lumen localization.
    action: ACCEPT
    reason: >-
      Correct lysosomal-lumen localization for GM2A acting within the
      glycosphingolipid catabolism pathway.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840833
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to lysosomal lumen (bHEXA,bHEXB hydrolyze
      GM2A-GA2 to GM2A-LacCer). Correct functional compartment; duplicate
      lysosomal-lumen localization.
    action: ACCEPT
    reason: >-
      Correct lysosomal-lumen localization for GM2A as it assists GA2 breakdown
      by hexosaminidases.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840884
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable annotation to lysosomal lumen (bHEXA,bHEXS hydrolyze
      GM2A-SM2). Correct functional compartment; duplicate lysosomal-lumen
      localization.
    action: ACCEPT
    reason: >-
      Correct lysosomal-lumen localization for GM2A assisting hexosaminidase
      hydrolysis of the sulfated glycolipid SM2.
    supported_by:
    - reference_id: file:human/GM2A/GM2A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
core_functions:
- description: >-
    GM2A is a lysosomal lipid chaperone (GM2 activator protein) that binds a
    single ganglioside GM2 molecule, extracts it from the intralysosomal luminal
    vesicle membrane, and presents the soluble GM2-GM2A complex to
    beta-hexosaminidase A (HEXA/HEXB) as the obligatory non-catalytic cofactor
    enabling hydrolysis of GM2 to GM3.
  molecular_function:
    id: GO:7770043
    label: lipid chaperone activity
  directly_involved_in:
  - id: GO:0006689
    label: ganglioside catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:11707436
    supporting_text: >-
      Hydrolysis of membrane-bound SM2 by the recombinant Hex S was
      synergistically stimulated by the GM2 activator protein
  - reference_id: file:human/GM2A/GM2A-uniprot.txt
    supporting_text: >-
      Extracts single GM2 molecules from intralysosomal luminal vesicle (ILV)
      membranes and presents them in
- description: >-
    Beyond GM2, GM2A functions as a lysosomal sphingolipid activator protein
    that mobilizes and solubilizes membrane glycosphingolipids (including the
    neutral glycolipid GA2) and presents them to hexosaminidases, contributing
    to glycosphingolipid catabolism; this lipid-mobilizing activity is tuned by
    the surrounding membrane lipid composition.
  molecular_function:
    id: GO:0030290
    label: sphingolipid activator protein activity
  directly_involved_in:
  - id: GO:0046479
    label: glycosphingolipid catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:30988135
    supporting_text: >-
      hydrolysis-inhibiting lipids also had an inhibiting effect on the
      solubilization and mobilization of membrane-bound lipids by the GM2
      activator protein
  - reference_id: file:human/GM2A/GM2A-uniprot.txt
    supporting_text: >-
      Also stimulates the breakdown of glycolipid GA2 by HEXA
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond GM2 and GA2, what is the full physiological repertoire of lipids that
    human GM2A binds and presents in vivo, and how significant is its reported
    cholesterol-transfer activity relative to NPC2?
- question: >-
    How does the intralysosomal membrane lipid milieu (BMP/anionic lipids,
    cholesterol, ceramide, sphingoid bases) quantitatively set the rate of
    GM2A-dependent GM2 catabolism in neurons, and could modulating it be
    therapeutic in the GM2 gangliosidosis AB variant?
suggested_experiments:
- description: >-
    Reconstitute GM2 hydrolysis on defined ILV-mimetic liposomes with purified
    GM2A and HexA while systematically varying BMP, cholesterol, and ceramide to
    map the lipid-dependence of GM2A substrate presentation.
- description: >-
    Use structural and single-molecule approaches (building on the beta-cup
    crystal structures) to capture GM2A in the act of extracting GM2 from a
    membrane and handing it to HexA, defining the transfer intermediate.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- 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: []
- 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: file:human/GM2A/GM2A-uniprot.txt
  title: UniProtKB entry P17900 (SAP3_HUMAN), Ganglioside GM2 activator
  findings: []
- id: PMID:11707436
  title: Physiological substrates for human lysosomal beta -hexosaminidase S.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache; abstract explicitly states that hydrolysis of
      membrane-bound SM2 by Hex S was synergistically stimulated by the GM2
      activator protein, supporting GM2A's activator/lipid-chaperone role in
      glycosphingolipid catabolism.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput urinary-exosome proteomics; supports only the non-core
      extracellular-exosome localization of GM2A, not its function.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput exosome proteomics; supports only the non-core
      extracellular-exosome localization.
- id: PMID:27498570
  title: Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Establishes endolysosomes as the principal sites of acid hydrolase
      activity; used as the basis for the curator IC placing GM2A at the
      endolysosomal ILV membrane. Not GM2A-specific but contextually apt.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 2.0 high-throughput AP-MS interactome; underlies a generic
      protein-binding IPI (partner ACTA2) that is over-annotated for GM2A.
- id: PMID:30988135
  title: Membrane lipids and their degradation compounds control GM2 catabolism at
    intralysosomal luminal vesicles.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary reconstitution study directly demonstrating GM2A-assisted GM2
      catabolism and its regulation by membrane lipids; strongest support for the
      lipid chaperone / ganglioside catabolic core functions.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 high-throughput AP-MS interactome; underlies a generic
      protein-binding IPI (partner ACTA2) that is over-annotated for GM2A.
- id: Reactome:R-HSA-1605595
  title: bHEXA hydrolyzes GM2A:GM2 to GM2A:GM3
  findings: []
- id: Reactome:R-HSA-1605624
  title: Beta-galactosidases hydrolyse mobilized GM1 to mobilized GM2
  findings: []
- id: Reactome:R-HSA-1605717
  title: GM2A binds and mobilizes ligands
  findings: []
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9840310
  title: Glycosphingolipid catabolism
  findings: []
- id: Reactome:R-HSA-9840795
  title: Beta-galactosidases hydrolyze GM2A:GA1 to GM2A:GA2
  findings: []
- id: Reactome:R-HSA-9840833
  title: bHEXA,bHEXB hydrolyze GM2A:GA2 to GM2A:LacCer
  findings: []
- id: Reactome:R-HSA-9840884
  title: bHEXA,bHEXS hydrolyze GM2A:SM2
  findings: []