SCARB2 (LIMP-2) is an abundant, heavily glycosylated type III double-pass membrane protein of the CD36/SR-B family whose large luminal domain, containing a hydrophobic tunnel, faces the lumen of the endosome-lysosome system. It resides principally in the limiting membrane of lysosomes and late endosomes, where it serves as the mannose-6-phosphate-independent sorting receptor that binds newly synthesized glucosylceramidase (GBA1) in the endoplasmic reticulum through a coiled-coil segment of its luminal domain and delivers it to the lysosome; loss of SCARB2 depletes lysosomal GBA1 activity. Lipid binding switches its oligomeric state - a crystal structure of the luminal domain dimer with bound cholesterol and phosphatidylcholine shows that lipid binding converts the GBA1-binding monomer into a dimer that prefers phosphatidylserine - and LIMP-2 facilitates phospholipid transport in cells. Overexpression enlarges endosomes and lysosomes, indicating a role in organelle biogenesis. A minor cell-surface pool serves as the entry receptor for enterovirus 71. Biallelic loss-of-function mutations cause action myoclonus-renal failure syndrome, and SCARB2 variants modify Parkinson disease and Gaucher disease phenotypes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | KEEP AS NON CORE | Summary: SCARB2 transits the Golgi during biosynthesis. Reason: As a glycoprotein destined for the lysosomal membrane, SCARB2 passes through the Golgi with its GBA1 cargo; a biosynthetic transit compartment rather than its site of action. |
| GO:0001786 phosphatidylserine binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The LIMP-2 luminal domain dimer binds phosphatidylserine preferentially. Reason: Structural and cellular work shows lipid binding with a preference for anionic phosphatidylserine, and LIMP-2 promotes its uptake; a genuine secondary activity alongside the core GBA1 receptor function. Supporting Evidence: PMID:29199275 Binding of these lipids alters LIMP-2 from functioning as a glucocerebrosidase-binding monomer toward a dimeric state that preferentially binds anionic phosphatidylserine over neutral phosphatidylcholine. |
| GO:0001786 phosphatidylserine binding | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | KEEP AS NON CORE | Summary: The LIMP-2 luminal domain dimer binds phosphatidylserine preferentially. Reason: Structural and cellular work shows lipid binding with a preference for anionic phosphatidylserine, and LIMP-2 promotes its uptake; a genuine secondary activity alongside the core GBA1 receptor function. Supporting Evidence: PMID:29199275 Binding of these lipids alters LIMP-2 from functioning as a glucocerebrosidase-binding monomer toward a dimeric state that preferentially binds anionic phosphatidylserine over neutral phosphatidylcholine. |
| GO:0004888 transmembrane signaling receptor activity | TAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | MODIFY | Summary: Transmembrane signalling receptor activity asserted in a review. Reason: SCARB2 is not a signalling receptor; it is a sorting/cargo receptor that binds GBA1 in the lumen and delivers it to the lysosome. The supported molecular function is cargo receptor activity, which this gene already carries with experimental evidence. Proposed replacements: cargo receptor activity Supporting Evidence: PMID:25202012 LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome |
| GO:0005044 scavenger receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: Scavenger receptor activity propagated from the CD36/SR-B ancestral node. Reason: The node assertion fits CD36 and SCARB1, which bind modified lipoproteins and fatty acids at the cell surface, but SCARB2 has diverged - it works inside the endolysosomal system as the sorting receptor for glucosylceramidase and has no established scavenging ligand. The supported molecular function for this member is cargo receptor activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000230217 SUPPORTS SOURCE BUT NOT TARGET The scavenger-receptor activity of the CD36/SR-BI members of this family is well supported, but SCARB2 acts in the lumen of the endolysosomal system as a cargo receptor, so the activity does not transfer to this member. Proposed replacements: cargo receptor activity Supporting Evidence: PMID:29199275 LIMP-2 is a receptor for the trafficking of glucocerebrosidase (GCase) from the endoplasmic reticulum to lysosomes |
| GO:0005044 scavenger receptor activity | IEA GO_REF:0000120 | MODIFY | Summary: Scavenger receptor activity inherited from the CD36/SR-B family. Reason: The family inference is understandable - CD36 and SR-BI are scavenger receptors - but SCARB2 has diverged - it has no established role in binding modified lipoproteins or scavenging extracellular ligands, and acts instead as a lumenal cargo receptor and lipid binding protein inside the endolysosomal system. Proposed replacements: cargo receptor activity Supporting Evidence: PMID:29199275 LIMP-2 is a receptor for the trafficking of glucocerebrosidase (GCase) from the endoplasmic reticulum to lysosomes |
| GO:0005044 scavenger receptor activity | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | MODIFY | Summary: Scavenger receptor activity inherited from the CD36/SR-B family. Reason: The family inference is understandable - CD36 and SR-BI are scavenger receptors - but SCARB2 has diverged - it has no established role in binding modified lipoproteins or scavenging extracellular ligands, and acts instead as a lumenal cargo receptor and lipid binding protein inside the endolysosomal system. Proposed replacements: cargo receptor activity Supporting Evidence: PMID:29199275 LIMP-2 is a receptor for the trafficking of glucocerebrosidase (GCase) from the endoplasmic reticulum to lysosomes |
| GO:0005044 scavenger receptor activity | TAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | MODIFY | Summary: Scavenger receptor activity inherited from the CD36/SR-B family. Reason: The family inference is understandable - CD36 and SR-BI are scavenger receptors - but SCARB2 has diverged - it has no established role in binding modified lipoproteins or scavenging extracellular ligands, and acts instead as a lumenal cargo receptor and lipid binding protein inside the endolysosomal system. Proposed replacements: cargo receptor activity Supporting Evidence: PMID:29199275 LIMP-2 is a receptor for the trafficking of glucocerebrosidase (GCase) from the endoplasmic reticulum to lysosomes |
| GO:0005515 protein binding | IPI PMID:24162852 Structure of LIMP-2 provides functional insights with implic... | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Generic protein binding from interactome screens and binary assays. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interaction, with the enzyme GBA1, is captured by enzyme binding and cargo receptor activity. |
| GO:0005764 lysosome | IEA GO_REF:0000002 | TOO GENERAL | Summary: Lysosome localization. Reason: True but entailed by the lysosomal membrane localization asserted with direct evidence in this review. |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: SCARB2 is an integral protein of the lysosomal membrane. Reason: This is the principal and best-documented location, established by organelle proteomics, immunolocalization and UniProt curation. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:7509809}; Multi-pass membrane protein PMID:12356916 LGP85 (LIMP II) is a type III transmembrane glycoprotein that is located primarily in the limiting membranes of lysosomes and late endosomes. |
| GO:0005765 lysosomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SCARB2 is an integral protein of the lysosomal membrane. Reason: This is the principal and best-documented location, established by organelle proteomics, immunolocalization and UniProt curation. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:7509809}; Multi-pass membrane protein PMID:12356916 LGP85 (LIMP II) is a type III transmembrane glycoprotein that is located primarily in the limiting membranes of lysosomes and late endosomes. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: SCARB2 is an integral protein of the lysosomal membrane. Reason: This is the principal and best-documented location, established by organelle proteomics, immunolocalization and UniProt curation. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:7509809}; Multi-pass membrane protein PMID:12356916 LGP85 (LIMP II) is a type III transmembrane glycoprotein that is located primarily in the limiting membranes of lysosomes and late endosomes. |
| GO:0005765 lysosomal membrane | IPI PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | ACCEPT | Summary: SCARB2 is an integral protein of the lysosomal membrane. Reason: This is the principal and best-documented location, established by organelle proteomics, immunolocalization and UniProt curation. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:7509809}; Multi-pass membrane protein PMID:12356916 LGP85 (LIMP II) is a type III transmembrane glycoprotein that is located primarily in the limiting membranes of lysosomes and late endosomes. |
| GO:0005765 lysosomal membrane | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: SCARB2 is an integral protein of the lysosomal membrane. Reason: This is the principal and best-documented location, established by organelle proteomics, immunolocalization and UniProt curation. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:7509809}; Multi-pass membrane protein PMID:12356916 LGP85 (LIMP II) is a type III transmembrane glycoprotein that is located primarily in the limiting membranes of lysosomes and late endosomes. |
| GO:0005765 lysosomal membrane | TAS PMID:12356916 A role for the lysosomal membrane protein LGP85 in the bioge... | ACCEPT | Summary: SCARB2 is an integral protein of the lysosomal membrane. Reason: This is the principal and best-documented location, established by organelle proteomics, immunolocalization and UniProt curation. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:7509809}; Multi-pass membrane protein PMID:12356916 LGP85 (LIMP II) is a type III transmembrane glycoprotein that is located primarily in the limiting membranes of lysosomes and late endosomes. |
| GO:0005765 lysosomal membrane | TAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: SCARB2 is an integral protein of the lysosomal membrane. Reason: This is the principal and best-documented location, established by organelle proteomics, immunolocalization and UniProt curation. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:17897319, ECO:0000269|PubMed:18022370, ECO:0000269|PubMed:7509809}; Multi-pass membrane protein PMID:12356916 LGP85 (LIMP II) is a type III transmembrane glycoprotein that is located primarily in the limiting membranes of lysosomes and late endosomes. |
| GO:0005789 endoplasmic reticulum membrane | TAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: SCARB2 binds its GBA1 cargo in the endoplasmic reticulum. Reason: The receptor engages newly synthesized glucocerebrosidase in the ER before transport, so the ER membrane is a functionally relevant location, not merely transit. Supporting Evidence: PMID:29199275 LIMP-2 is a receptor for the trafficking of glucocerebrosidase (GCase) from the endoplasmic reticulum to lysosomes |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866277 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867754 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867756 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868071 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868072 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868230 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868236 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868648 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868651 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: A minor cell-surface pool of SCARB2 exists and is used by enterovirus 71. Reason: The protein functions predominantly in the lysosomal and late endosomal membrane; the plasma-membrane pool is small but real and is the entry receptor exploited by EV71, which also makes it accessible from outside the cell. Supporting Evidence: file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: (Microbial infection) Acts as a receptor for enterovirus 71. |
| GO:0005925 focal adhesion | HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome... | MARK AS OVER ANNOTATED | Summary: SCARB2 detected in a focal adhesion proteome. Reason: A single high-throughput fractionation hit for an abundant lysosomal membrane protein; there is no evidence that SCARB2 functions at focal adhesions. |
| GO:0006622 protein targeting to lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: SCARB2 targets glucosylceramidase to the lysosome. Reason: Loss of LIMP-2 severely reduces lysosomal GBA1 protein and activity, and the luminal coiled-coil binds the enzyme - this is the defining process for SCARB2. Supporting Evidence: PMID:18022370 Affinity-chromatography experiments revealed that the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. PMID:18022370 beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. |
| GO:0006622 protein targeting to lysosome | IEA GO_REF:0000107 | ACCEPT | Summary: SCARB2 targets glucosylceramidase to the lysosome. Reason: Loss of LIMP-2 severely reduces lysosomal GBA1 protein and activity, and the luminal coiled-coil binds the enzyme - this is the defining process for SCARB2. Supporting Evidence: PMID:18022370 Affinity-chromatography experiments revealed that the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. PMID:18022370 beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. |
| GO:0006622 protein targeting to lysosome | IMP PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: SCARB2 targets glucosylceramidase to the lysosome. Reason: Loss of LIMP-2 severely reduces lysosomal GBA1 protein and activity, and the luminal coiled-coil binds the enzyme - this is the defining process for SCARB2. Supporting Evidence: PMID:18022370 Affinity-chromatography experiments revealed that the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. PMID:18022370 beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. |
| GO:0006622 protein targeting to lysosome | NAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: SCARB2 targets glucosylceramidase to the lysosome. Reason: Loss of LIMP-2 severely reduces lysosomal GBA1 protein and activity, and the luminal coiled-coil binds the enzyme - this is the defining process for SCARB2. Supporting Evidence: PMID:18022370 Affinity-chromatography experiments revealed that the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. PMID:18022370 beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. |
| GO:0006898 receptor-mediated endocytosis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SCARB2 participates in endocytic uptake. Reason: Internalization from the cell surface delivers SCARB2 (and EV71, and phospholipids) to the endolysosomal system; secondary to the intracellular sorting role. |
| GO:0006898 receptor-mediated endocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCARB2 participates in endocytic uptake. Reason: Internalization from the cell surface delivers SCARB2 (and EV71, and phospholipids) to the endolysosomal system; secondary to the intracellular sorting role. |
| GO:0006898 receptor-mediated endocytosis | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | KEEP AS NON CORE | Summary: SCARB2 participates in endocytic uptake. Reason: Internalization from the cell surface delivers SCARB2 (and EV71, and phospholipids) to the endolysosomal system; secondary to the intracellular sorting role. |
| GO:0006914 autophagy | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCARB2 influences autophagy. Reason: Loss of an abundant lysosomal membrane protein affects autophagic flux indirectly; SCARB2 is not a component of the autophagy machinery. |
| GO:0010008 endosome membrane | TAS PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: SCARB2 is present in endosome membranes. Reason: Consistent with its late endosomal and lysosomal distribution and with its trafficking route; supported by direct localization studies. Supporting Evidence: PMID:12356916 located primarily in the limiting membranes of lysosomes and late endosomes |
| GO:0010976 positive regulation of neuron projection development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCARB2 supports neurite outgrowth in rodent neurons. Reason: A neuronal phenotype downstream of lysosomal function; indirect. |
| GO:0015485 cholesterol binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The LIMP-2 luminal domain binds cholesterol. Reason: Cholesterol was resolved in the crystal structure of the luminal domain dimer; a real secondary lipid-binding property. Supporting Evidence: PMID:29199275 Here we report a crystal structure of a LIMP-2 luminal domain dimer with bound cholesterol and phosphatidylcholine. |
| GO:0015485 cholesterol binding | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | KEEP AS NON CORE | Summary: The LIMP-2 luminal domain binds cholesterol. Reason: Cholesterol was resolved in the crystal structure of the luminal domain dimer; a real secondary lipid-binding property. Supporting Evidence: PMID:29199275 Here we report a crystal structure of a LIMP-2 luminal domain dimer with bound cholesterol and phosphatidylcholine. |
| GO:0015917 aminophospholipid transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LIMP-2 facilitates phospholipid transport into cells. Reason: Cellular uptake experiments show LIMP-2-dependent transport of phospholipids with a preference for phosphatidylserine, consistent with the hydrophobic tunnel through its luminal domain; secondary to the GBA1 receptor function. Supporting Evidence: PMID:29199275 In cellular uptake experiments, LIMP-2 facilitates transport of phospholipids into murine fibroblasts, with a strong substrate preference for phosphatidylserine. |
| GO:0015917 aminophospholipid transport | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | KEEP AS NON CORE | Summary: LIMP-2 facilitates phospholipid transport into cells. Reason: Cellular uptake experiments show LIMP-2-dependent transport of phospholipids with a preference for phosphatidylserine, consistent with the hydrophobic tunnel through its luminal domain; secondary to the GBA1 receptor function. Supporting Evidence: PMID:29199275 In cellular uptake experiments, LIMP-2 facilitates transport of phospholipids into murine fibroblasts, with a strong substrate preference for phosphatidylserine. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Generic membrane localization. Reason: Correct but too general; SCARB2 is an integral protein of the lysosomal and late endosomal membrane, terms already carried with direct evidence. Proposed replacements: lysosomal membrane late endosome membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane localization. Reason: Correct but too general; SCARB2 is an integral protein of the lysosomal and late endosomal membrane, terms already carried with direct evidence. Proposed replacements: lysosomal membrane late endosome membrane |
| GO:0016020 membrane | TAS PMID:1374238 Isolation and sequencing of a cDNA clone encoding the 85 kDa... | MODIFY | Summary: Generic membrane localization. Reason: Correct but too general; SCARB2 is an integral protein of the lysosomal and late endosomal membrane, terms already carried with direct evidence. Proposed replacements: lysosomal membrane late endosome membrane |
| GO:0019377 glycolipid catabolic process | NAS PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | KEEP AS NON CORE | Summary: SCARB2 supports glycolipid catabolism by delivering GBA1. Reason: The catabolic step is performed by glucosylceramidase; SCARB2 delivers the enzyme, so it enables rather than executes glycolipid breakdown. Supporting Evidence: PMID:18022370 beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | ACCEPT | Summary: SCARB2 binds the enzyme glucosylceramidase. Reason: Direct affinity chromatography and mapping of the binding sequences establish a specific enzyme-receptor interaction, which is the mechanism of its cargo receptor function. Supporting Evidence: PMID:18022370 the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. This interaction involves a coiled-coil domain within the lumenal domain. |
| GO:0019899 enzyme binding | IPI PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: SCARB2 binds the enzyme glucosylceramidase. Reason: Direct affinity chromatography and mapping of the binding sequences establish a specific enzyme-receptor interaction, which is the mechanism of its cargo receptor function. Supporting Evidence: PMID:18022370 the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. This interaction involves a coiled-coil domain within the lumenal domain. |
| GO:0019899 enzyme binding | IPI PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: SCARB2 binds the enzyme glucosylceramidase. Reason: Direct affinity chromatography and mapping of the binding sequences establish a specific enzyme-receptor interaction, which is the mechanism of its cargo receptor function. Supporting Evidence: PMID:18022370 the lysosomal integral membrane protein LIMP-2 is a specific binding partner of beta-glucocerebrosidase. This interaction involves a coiled-coil domain within the lumenal domain. |
| GO:0030666 endocytic vesicle membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCARB2 is present on endocytic vesicle membranes. Reason: Part of the trafficking itinerary between the cell surface and the lysosome; peripheral. |
| GO:0030666 endocytic vesicle membrane | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | KEEP AS NON CORE | Summary: SCARB2 is present on endocytic vesicle membranes. Reason: Part of the trafficking itinerary between the cell surface and the lysosome; peripheral. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868658 | KEEP AS NON CORE | Summary: Reactome places SCARB2 on clathrin-coated endocytic vesicle membranes. Reason: Reflects clathrin-dependent internalization of the surface pool; a transit compartment. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868659 | KEEP AS NON CORE | Summary: Reactome places SCARB2 on clathrin-coated endocytic vesicle membranes. Reason: Reflects clathrin-dependent internalization of the surface pool; a transit compartment. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868660 | KEEP AS NON CORE | Summary: Reactome places SCARB2 on clathrin-coated endocytic vesicle membranes. Reason: Reflects clathrin-dependent internalization of the surface pool; a transit compartment. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: Reactome places SCARB2 on clathrin-coated endocytic vesicle membranes. Reason: Reflects clathrin-dependent internalization of the surface pool; a transit compartment. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8869438 | KEEP AS NON CORE | Summary: Reactome places SCARB2 on clathrin-coated endocytic vesicle membranes. Reason: Reflects clathrin-dependent internalization of the surface pool; a transit compartment. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871193 | KEEP AS NON CORE | Summary: Reactome places SCARB2 on clathrin-coated endocytic vesicle membranes. Reason: Reflects clathrin-dependent internalization of the surface pool; a transit compartment. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871194 | KEEP AS NON CORE | Summary: Reactome places SCARB2 on clathrin-coated endocytic vesicle membranes. Reason: Reflects clathrin-dependent internalization of the surface pool; a transit compartment. |
| GO:0031210 phosphatidylcholine binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The LIMP-2 luminal domain binds phosphatidylcholine. Reason: Phosphatidylcholine is resolved in the luminal domain dimer structure, though the dimer prefers phosphatidylserine; a secondary lipid-binding property. Supporting Evidence: PMID:29199275 Here we report a crystal structure of a LIMP-2 luminal domain dimer with bound cholesterol and phosphatidylcholine. |
| GO:0031210 phosphatidylcholine binding | ISS PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | KEEP AS NON CORE | Summary: The LIMP-2 luminal domain binds phosphatidylcholine. Reason: Phosphatidylcholine is resolved in the luminal domain dimer structure, though the dimer prefers phosphatidylserine; a secondary lipid-binding property. Supporting Evidence: PMID:29199275 Here we report a crystal structure of a LIMP-2 luminal domain dimer with bound cholesterol and phosphatidylcholine. |
| GO:0031902 late endosome membrane | TAS PMID:12356916 A role for the lysosomal membrane protein LGP85 in the bioge... | ACCEPT | Summary: SCARB2 is in the limiting membrane of late endosomes. Reason: Direct localization studies place LGP85/LIMP-2 in late endosomal as well as lysosomal limiting membranes. Supporting Evidence: PMID:12356916 located primarily in the limiting membranes of lysosomes and late endosomes |
| GO:0038024 cargo receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: SCARB2 is the sorting receptor for glucosylceramidase. Reason: It binds GBA1 in the ER lumen and releases it in the acidic lysosome, the textbook definition of a cargo receptor; loss of SCARB2 mislocalizes and destabilizes the enzyme. Supporting Evidence: PMID:25202012 LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting. |
| GO:0038024 cargo receptor activity | IMP PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: SCARB2 is the sorting receptor for glucosylceramidase. Reason: It binds GBA1 in the ER lumen and releases it in the acidic lysosome, the textbook definition of a cargo receptor; loss of SCARB2 mislocalizes and destabilizes the enzyme. Supporting Evidence: PMID:25202012 LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome file:human/SCARB2/SCARB2-uniprot.txt FUNCTION: Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting. |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: SCARB2 luminal domains dimerize. Reason: The crystal structure resolves a luminal domain dimer, and lipid binding drives the monomer-to-dimer switch that changes partner selection. Supporting Evidence: PMID:29199275 Here we report a crystal structure of a LIMP-2 luminal domain dimer with bound cholesterol and phosphatidylcholine. |
| GO:0042803 protein homodimerization activity | IPI PMID:29199275 Lysosomal integral membrane protein-2 as a phospholipid rece... | ACCEPT | Summary: SCARB2 luminal domains dimerize. Reason: The crystal structure resolves a luminal domain dimer, and lipid binding drives the monomer-to-dimer switch that changes partner selection. Supporting Evidence: PMID:29199275 Here we report a crystal structure of a LIMP-2 luminal domain dimer with bound cholesterol and phosphatidylcholine. |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The large luminal domain of SCARB2 faces the lysosomal lumen. Reason: Describes the orientation of a membrane protein rather than a soluble lumenal pool; true but secondary to lysosomal membrane. |
| GO:0043202 lysosomal lumen | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | KEEP AS NON CORE | Summary: The large luminal domain of SCARB2 faces the lysosomal lumen. Reason: Describes the orientation of a membrane protein rather than a soluble lumenal pool; true but secondary to lysosomal membrane. |
| GO:0043470 regulation of carbohydrate catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCARB2 sets lysosomal glucosylceramidase activity and hence glycoside catabolism. Reason: Regulation here is indirect - through delivery of the hydrolase - rather than through an activity of SCARB2 on the catabolic step. Supporting Evidence: PMID:18022370 beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. |
| GO:0043470 regulation of carbohydrate catabolic process | IMP PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | KEEP AS NON CORE | Summary: SCARB2 sets lysosomal glucosylceramidase activity and hence glycoside catabolism. Reason: Regulation here is indirect - through delivery of the hydrolase - rather than through an activity of SCARB2 on the catabolic step. Supporting Evidence: PMID:18022370 beta-glucocerebrosidase activity and protein levels were severely decreased in LIMP-2-deficient mouse tissues. |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCARB2 binds chaperone proteins. Reason: Electronically transferred and generic; the informative binding activity is the specific interaction with GBA1. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: SCARB2 detected in exosome preparations. Reason: Common proteomic finding for abundant endolysosomal membrane proteins; peripheral. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: SCARB2 detected in exosome preparations. Reason: Common proteomic finding for abundant endolysosomal membrane proteins; peripheral. |
| GO:1904978 regulation of endosome organization | TAS PMID:12356916 A role for the lysosomal membrane protein LGP85 in the bioge... | ACCEPT | Summary: SCARB2 levels control endosome morphology. Reason: Overexpression of LGP85/LIMP-2 enlarges early and late endosomes, an effect not seen with other abundant lysosomal membrane proteins, indicating a specific role in endosome organization. Supporting Evidence: PMID:12356916 Here we demonstrate that overexpression of LGP85 causes an enlargement of early endosomes and late endosomes/lysosomes. |
| GO:1905671 regulation of lysosome organization | TAS PMID:12356916 A role for the lysosomal membrane protein LGP85 in the bioge... | ACCEPT | Summary: SCARB2 levels control lysosome morphology. Reason: The same overexpression experiments enlarge late endosomes and lysosomes specifically, supporting a role in lysosome organization. Supporting Evidence: PMID:12356916 Such a morphological alteration was not observed by overexpression of other lysosomal membrane proteins |
| GO:2000752 regulation of glucosylceramide catabolic process | TAS PMID:25584808 Identification of miRNAs that modulate glucocerebrosidase ac... | KEEP AS NON CORE | Summary: SCARB2 regulates glucosylceramide catabolism by delivering GBA1. Reason: Indirect regulation through enzyme delivery; the hydrolysis itself is carried out by glucosylceramidase. |
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Download this section (compressed HTML)Q: Is the lipid-transport activity of LIMP-2 physiologically significant in human lysosomes, or is it chiefly a regulatory switch controlling GBA1 binding through the monomer-dimer equilibrium?
Q: How large is the cell-surface pool of SCARB2 in human tissues, and is it regulated, given that it determines susceptibility to enterovirus 71 entry?
Q: Does SCARB2 carry cargo other than GBA1 to the lysosome?
Experiment: Quantitative surface biotinylation plus total membrane proteomics across human cell types to measure the fraction of SCARB2 at the plasma membrane and whether it changes with lysosomal stress or EV71 infection.
Experiment: Structure-guided mutants that block the luminal hydrophobic tunnel but preserve GBA1 binding, assayed for lysosomal phospholipid composition and GBA1 delivery, to separate the two activities.
Experiment: Proteomic comparison of lysosomal content in SCARB2-null versus wild-type human cells to test whether other hydrolases depend on SCARB2 for delivery.
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