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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005319 lipid carrier activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Lipid-binding and transfer protein essential for lysosomal degradation of ganglioside GM2. |
| GO:0006689 ganglioside catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred involvement in ganglioside catabolism. This is the central biological process for GM2A, which is obligatory for lysosomal GM2 degradation. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Lipid-binding and transfer protein essential for lysosomal degradation of ganglioside GM2. |
| GO:0006869 lipid transport | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Possesses dual function: membrane lipid mobilization/solubilization and lipid substrate presentation to hydrolases |
| GO:0009898 cytoplasmic side of plasma membrane | IBA GO_REF:0000033 | REMOVE | 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. 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 Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to lysosome. This is the primary and correct site of GM2A function. Reason: GM2A is a lysosomal protein; its function (GM2 mobilization and presentation to HexA) occurs in the lysosome. Consistent with the curated subcellular location. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0006689 ganglioside catabolic process | IEA GO_REF:0000002 | ACCEPT | 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. Reason: The GM2-AP family signature reliably predicts a role in ganglioside catabolism; agrees with the experimental and phylogenetic annotations. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Lipid-binding and transfer protein essential for lysosomal degradation of ganglioside GM2. |
| GO:0008047 enzyme activator activity | IEA GO_REF:0000120 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Forms a stoichiometric GM2-GM2A complex that serves as the substrate for HEXA |
| GO:0046479 glycosphingolipid catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA mapping to glycosphingolipid catabolic process. GM2A assists degradation of glycosphingolipids (GM2 and the neutral glycolipid GA2), so this broader process is accurate. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Also stimulates the breakdown of glycolipid GA2 by HEXA |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | 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). 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. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0001573 ganglioside metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Lipid-binding and transfer protein essential for lysosomal degradation of ganglioside GM2. |
| GO:0005319 lipid carrier activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara ortholog transfer of lipid carrier activity, redundant with the IBA annotation to the same term. Correct molecular function. Reason: Duplicate of the accepted lipid carrier activity annotation; GM2A binds and delivers GM2 (and other lipids), matching the term. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Lipid-binding and transfer protein essential for lysosomal degradation of ganglioside GM2. |
| GO:0006869 lipid transport | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. Reason: GM2A mobilizes/transfers lipids, but its biological role is substrate mobilization within catabolism; retain lipid transport as non-core. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Possesses dual function: membrane lipid mobilization/solubilization and lipid substrate presentation to hydrolases |
| GO:0009898 cytoplasmic side of plasma membrane | IEA GO_REF:0000107 | REMOVE | 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). 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 Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0016004 phospholipase activator activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Exhibits some calcium-independent phospholipase activity |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara ortholog transfer to apical plasma membrane. As with the basolateral record, a possible surface pool but not the functional lysosomal site. Reason: Non-core surface/secretory localization inferred from the rodent ortholog; GM2A's characterized activity is lysosomal. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0032428 beta-N-acetylgalactosaminidase activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt presents them in soluble form to beta-hexosaminidase A (HEXA) for cleavage of N-acetyl- |
| GO:0006689 ganglioside catabolic process | IDA PMID:11707436 Physiological substrates for human lysosomal beta -hexosamin... | ACCEPT | 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. 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. Supporting Evidence: PMID:11707436 Hydrolysis of membrane-bound SM2 by the recombinant Hex S was synergistically stimulated by the GM2 activator protein |
| GO:0160317 endolysosomal intralumenal vesicle membrane | IC PMID:11707436 Physiological substrates for human lysosomal beta -hexosamin... | ACCEPT | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Extracts single GM2 molecules from intralysosomal luminal vesicle (ILV) membranes |
| GO:7770043 lipid chaperone activity | IDA PMID:11707436 Physiological substrates for human lysosomal beta -hexosamin... | ACCEPT | 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. 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. Supporting Evidence: PMID:11707436 Hydrolysis of membrane-bound SM2 by the recombinant Hex S was synergistically stimulated by the GM2 activator protein file:human/GM2A/GM2A-uniprot.txt Extracts single GM2 molecules from intralysosomal luminal vesicle (ILV) membranes |
| GO:0046479 glycosphingolipid catabolic process | TAS Reactome:R-HSA-9840310 | ACCEPT | Summary: Reactome pathway (Glycosphingolipid catabolism) annotation to glycosphingolipid catabolic process. Accurate for GM2A's role in degradation of GM2 and related glycosphingolipids. Reason: GM2A participates in Reactome's glycosphingolipid catabolism, presenting glycosphingolipid substrates to hexosaminidases; the broad catabolic process is correct. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Also stimulates the breakdown of glycolipid GA2 by HEXA |
| GO:0160317 endolysosomal intralumenal vesicle membrane | IC PMID:27498570 Endolysosomes Are the Principal Intracellular Sites of Acid ... | ACCEPT | 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. 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. Supporting Evidence: PMID:27498570 Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity file:human/GM2A/GM2A-uniprot.txt Extracts single GM2 molecules from intralysosomal luminal vesicle (ILV) membranes |
| GO:7770043 lipid chaperone activity | IDA PMID:30988135 Membrane lipids and their degradation compounds control GM2 ... | ACCEPT | 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. 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. Supporting Evidence: PMID:30988135 hydrolysis-inhibiting lipids also had an inhibiting effect on the solubilization and mobilization of membrane-bound lipids by the GM2 activator protein |
| GO:0006689 ganglioside catabolic process | IDA PMID:30988135 Membrane lipids and their degradation compounds control GM2 ... | ACCEPT | Summary: Direct experimental annotation to ganglioside catabolic process from the reconstituted GM2 catabolism system. Core, disease-relevant biological process for GM2A. 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. Supporting Evidence: PMID:30988135 incorporating lipids into the GM2-carrying membrane such as cholesterol, SM, sphingosine, and sphinganine inhibits GM2 hydrolysis by Ξ²-hexosaminidase A assisted by GM2 activator protein |
| GO:0030290 sphingolipid activator protein activity | TAS Reactome:R-HSA-1605717 | ACCEPT | Summary: Reactome traceable annotation to sphingolipid activator protein activity, the family-level cofactor activity for lysosomal sphingolipid degradation. Accurate for GM2A (SAP-3). 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt Forms a stoichiometric GM2-GM2A complex that serves as the substrate for HEXA |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: Reactome traceable annotation to azurophil granule lumen, via the neutrophil-degranulation pathway. A secretory-granule localization, not the primary lysosomal functional site. 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. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:23533145 exosome preparations were characterized by a shotgun proteomics procedure |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of GM2A in urinary exosomes. As above, a secreted/exosomal pool, non-core relative to its lysosomal function. 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. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1605595 | ACCEPT | Summary: Reactome traceable annotation to lysosomal lumen (bHEXA hydrolyzes GM2A-GM2 to GM2A-GM3). This is the primary, correct functional compartment for GM2A. Reason: GM2A operates as a soluble activator in the lysosomal lumen, where it presents GM2 to HexA. The lysosomal-lumen localization is well established. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1605624 | ACCEPT | Summary: Reactome traceable annotation to lysosomal lumen (beta-galactosidases hydrolyse mobilized GM1 to mobilized GM2). Correct functional compartment; duplicate lysosomal-lumen localization. Reason: Consistent, correct lysosomal-lumen localization for GM2A within the Reactome glycosphingolipid catabolism pathway. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1605717 | ACCEPT | Summary: Reactome traceable annotation to lysosomal lumen (GM2A binds and mobilizes ligands). Correct functional compartment; duplicate lysosomal-lumen localization. Reason: GM2A binds and mobilizes its lipid ligands within the lysosomal lumen; correct localization consistent with the other lysosomal-lumen records. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9840795 | ACCEPT | Summary: Reactome traceable annotation to lysosomal lumen (beta-galactosidases hydrolyze GM2A-GA1 to GM2A-GA2). Correct functional compartment; duplicate lysosomal-lumen localization. Reason: Correct lysosomal-lumen localization for GM2A acting within the glycosphingolipid catabolism pathway. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9840833 | ACCEPT | Summary: Reactome traceable annotation to lysosomal lumen (bHEXA,bHEXB hydrolyze GM2A-GA2 to GM2A-LacCer). Correct functional compartment; duplicate lysosomal-lumen localization. Reason: Correct lysosomal-lumen localization for GM2A as it assists GA2 breakdown by hexosaminidases. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9840884 | ACCEPT | Summary: Reactome traceable annotation to lysosomal lumen (bHEXA,bHEXS hydrolyze GM2A-SM2). Correct functional compartment; duplicate lysosomal-lumen localization. Reason: Correct lysosomal-lumen localization for GM2A assisting hexosaminidase hydrolysis of the sulfated glycolipid SM2. Supporting Evidence: file:human/GM2A/GM2A-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
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