LRP10 is a 713-residue type-I membrane sorting receptor with an extracellular region containing two CUB domains and four LDL-receptor class A repeats, a single transmembrane helix, and a long cytoplasmic tail. It cycles among the trans-Golgi network, plasma membrane, and early endosomes. In human cells its ectodomain binds amyloid-beta precursor protein (APP), while tail-dependent trafficking promotes APP return from endosomes to the Golgi and limits amyloidogenic processing. Endogenous human-brain expression is strongest in astrocytes and the neurovasculature, where LRP10 shares trafficking compartments and associates with SORL1. Mouse Lrp10 supports uptake of apoE-enriched beta-VLDL, providing ortholog-level evidence for lipoprotein particle receptor activity but not direct human uptake. Isoform 2 lacks residues 557-713 of the cytoplasmic tail, but no distinct isoform-specific function has been demonstrated.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: LRP10 can reach the plasma membrane as part of its itinerary through the secretory and endosomal systems, but plasma membrane is not its defining steady-state compartment. Reason: The PAINT source set spans many LDL-receptor-family proteins and is much broader than the LRP10-specific PTHR24270:SF17 subfamily. The transferred location is biologically defensible, but it should be retained as a secondary trafficking location rather than treated as LRP10's core site of action. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002557696 · broad LDL-receptor-family PAINT node SUPPORTS TRANSFER The mixed LDLR-family donor set supports access to the plasma membrane, but does not establish it as the principal compartment of LRP10. |
| GO:0005041 low-density lipoprotein particle receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: The phylogenetic inference is grounded in the mouse LRP10 ortholog, for which the available experiment tested uptake of apoE-enriched beta-VLDL rather than LDL particles generally. Reason: PMID:11123907 supports receptor-mediated lipoprotein uptake by mouse Lrp10 (then named LRP9), but one beta-VLDL assay does not establish a particle-class-specific human activity. GO:0030228 preserves the supported general lipoprotein-particle receptor function without claiming LDL or VLDL specificity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1929480 · mouse Lrp10 SUPPORTS TRANSFER Mouse Lrp10 supports transfer of lipoprotein-uptake activity to the two-member LRP10 subfamily, but the experiment was VLDL-specific. PANTHER:PTN008611683 · LRP10 PAINT node SUPPORTS TRANSFER The node supports orthologous transfer; the corrective issue is the particle-specific GO term, not paralog divergence. Proposed replacements: lipoprotein particle receptor activity Supporting Evidence: PMID:11123907 Apolipoprotein E (apoE)-enriched beta-VLDL stimulated cellular cholesteryl ester formation in ldl-A7/LRP9. |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: LRP10 is a single-pass type-I membrane protein, so the generic membrane localization inferred from sequence, UniProt localization, and the mouse ortholog is correct. Reason: A signal peptide and transmembrane helix establish LRP10 as an integral membrane receptor. GO:0016020 is broad but accurate, and the four ordered inference sources are concordant rather than over-specific. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028763 · ARBA membrane rule SUPPORTS TRANSFER UniProtKB:Q7TQH7 · mouse Lrp10 SUPPORTS TRANSFER ensembl:ENSMUSP00000022782 · mouse Lrp10 Ensembl protein SUPPORTS TRANSFER UniProtKB-SubCell:SL-0162 · UniProt membrane localization SUPPORTS TRANSFER Supporting Evidence: file:human/LRP10/LRP10-uniprot.txt TRANSMEM 441..461 |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000117 | ACCEPT | Summary: Vesicle-mediated transport is an appropriate broad process for a sorting receptor that cycles through membrane compartments and internalizes cargo. Reason: The ARBA inference is consistent with the receptor's membrane topology and internalization role. The term does not overstate a specific cargo, compartment, adaptor, or isoform, so the broad process is retained. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028249 · ARBA vesicle-mediated-transport rule SUPPORTS TRANSFER Supporting Evidence: file:human/LRP10/LRP10-uniprot.txt Probable receptor, which is involved in the internalization |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HuRI reports LRP10 binary-screen interactions with 21 diverse human proteins, aggregated here in their first-seen GOA order. Reason: The high-throughput binary interaction screen supports physical binding, but the heterogeneous partner set does not establish a shared LRP10-specific molecular function, physiological complex, or trafficking mechanism. Generic protein binding is therefore retained only as non-core; no evidence-supported specific replacement term covers this screen group. Supporting Evidence: PMID:32296183 To map the reference interactome, we performed nine screens of Space III, followed by pairwise verification by quadruplicate retesting and sequence confirmation. |
| GO:0005041 low-density lipoprotein particle receptor activity | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfers a lipoprotein-receptor activity from the mouse Lrp10 ortholog, but the underlying mouse experiment tested apoE-enriched beta-VLDL rather than LDL particles generally. Reason: Orthology within the narrow LRP10 subfamily supports transfer of the general lipoprotein-particle receptor function. GO:0030228 captures that supported essence without turning a single beta-VLDL assay into LDL- or VLDL-particle specificity for human LRP10. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q7TQH7 · mouse Lrp10 SUPPORTS TRANSFER The mouse ortholog supports transfer within PTHR24270:SF17, but the experimental cargo was apoE-enriched beta-VLDL. ensembl:ENSMUSP00000022782 · mouse Lrp10 Ensembl protein SUPPORTS TRANSFER The orthology is appropriate; only the transferred particle-specific GO term requires correction. Proposed replacements: lipoprotein particle receptor activity Supporting Evidence: PMID:11123907 Apolipoprotein E (apoE)-enriched beta-VLDL stimulated cellular cholesteryl ester formation in ldl-A7/LRP9. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: A membrane-proteome survey identified LRP10 in the membrane fraction of a human NK-like cell line. Reason: The HDA call is consistent with LRP10's independently established single-pass type-I membrane architecture. The cached record is abstract-only and does not expose the LRP10-specific peptide table, so the experimental curator's assignment is retained without extrapolating to a more specific membrane compartment. |
| GO:0038024 cargo receptor activity | IDA PMID:22734645 LDLR-related protein 10 (LRP10) regulates amyloid precursor ... | NEW | Summary: Proposed direct annotation of LRP10 as an APP cargo receptor: its ectodomain binds APP, and its cytoplasmic trafficking motifs control transport of the receptor-cargo pair through the endosome-Golgi route. Reason: Direct ectodomain binding, together with motif-dependent delivery of APP between transport compartments, satisfies cargo receptor activity more specifically than generic protein binding. APP is recorded as the supporting cargo; this does not imply that APP is LRP10's only cargo. Supporting Evidence: PMID:22734645 These results indicated that LRP10 interacts directly and predominantly with the ectodomain of APP in vitro. PMID:22734645 These results suggested that LRP10 moves through the secretory pathway to the cell surface. After rapid internalization in early endosomes, LRP10 is recycled back to the Golgi, a step that requires the DXXLL motifs in the cytoplasmic tail of LRP10 . |
| GO:0042147 retrograde transport, endosome to Golgi | IMP PMID:22734645 LDLR-related protein 10 (LRP10) regulates amyloid precursor ... | NEW | Summary: Proposed annotation for the directly tested DXXLL-motif-dependent return of LRP10, and associated APP cargo, from early endosomes to the Golgi. Reason: Cell-surface pulse-chase and the DXXLL-to-DXXAA trafficking mutant identify the endosome-to-Golgi step specifically; this is more informative than the existing broad vesicle-mediated transport annotation. Supporting Evidence: PMID:22734645 These results suggested that LRP10 moves through the secretory pathway to the cell surface. After rapid internalization in early endosomes, LRP10 is recycled back to the Golgi, a step that requires the DXXLL motifs in the cytoplasmic tail of LRP10 . |
| GO:0005802 trans-Golgi network | IDA PMID:33913039 LRP10 interacts with SORL1 in the intracellular vesicle traf... | NEW | Summary: Proposed direct localization annotation from endogenous human iPSC-derived astrocytes. Reason: The study directly places endogenous LRP10 at the trans-Golgi network in a physiologically relevant human cell type, refining the existing generic membrane annotation. Supporting Evidence: PMID:33913039 In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). |
| GO:1902430 negative regulation of amyloid-beta formation | IMP PMID:22734645 LDLR-related protein 10 (LRP10) regulates amyloid precursor ... | NEW | Summary: Proposed direct annotation for the reduction of amyloid-beta production caused by LRP10-dependent APP sorting in human SH-SY5Y cells. Reason: Increased LRP10 reduced APP processing into amyloid-beta, whereas LRP10 depletion increased amyloid-beta production. This bidirectional perturbation evidence directly supports negative regulation of amyloid-beta formation. Supporting Evidence: PMID:22734645 Increased expression of LRP10 in human neuroblastoma SH-SY5Y cells induces the accumulation of mature APP in the Golgi and reduces its presence at the cell surface and its processing into Aβ, while knockdown of LRP10 expression increases Aβ production. |
| GO:0005769 early endosome | IDA PMID:33913039 LRP10 interacts with SORL1 in the intracellular vesicle traf... | NEW | Summary: Proposed direct localization annotation from endogenous human iPSC-derived astrocytes. Reason: The study directly places endogenous LRP10 at early endosomes, a core compartment in its cargo-sorting itinerary. No retromer-complex membership is inferred from colocalization. Supporting Evidence: PMID:33913039 In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). |
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Download this section (compressed HTML)Q: Which endogenous human cargos, beyond APP, are directly bound and sorted by LRP10, and does human LRP10 mediate apoE-rich beta-VLDL uptake?
Q: Does SORL1 recruit LRP10 into a shared trafficking route, does LRP10 recruit SORL1, or do the two receptors associate indirectly through common machinery?
Q: How does deletion of residues 557-713 alter the localization, cargo binding, and transport kinetics of LRP10 isoform 2?
Q: Which trafficking defect caused by disease-associated LRP10 variants is necessary and sufficient to perturb alpha-synuclein handling in human brain cell types?
Experiment: Perform quantitative surface-cargo capture, internalization, and pulse-chase proteomics in endogenous LRP10-knockout and rescued human astrocytes, testing APP, apoE-rich beta-VLDL, and unbiased candidate cargos.
Hypothesis: Human LRP10 directly sorts a restricted cargo set that includes APP, while beta-VLDL uptake is cargo- and cell-context dependent rather than a general LDL-receptor-family property.
Type: Endogenous cargo-binding and trafficking assay
Experiment: Map the endogenous LRP10-SORL1 interface and combine acute depletion of each receptor with live-cell cargo tracking and rescue by interaction- or DXXLL-motif-defective alleles in human iPSC-derived astrocytes.
Hypothesis: LRP10 and SORL1 cooperate in endosome-to-Golgi cargo sorting without LRP10 functioning as an autonomous macromolecular adaptor.
Type: Endogenous interaction and epistasis analysis
Experiment: Introduce isoform-specific endogenous tags and compare full-length LRP10 with isoform 2 for organelle residence, APP sorting, SORL1 association, and surface recycling, using isoform-selective knockout and rescue.
Hypothesis: Loss of residues 557-713 changes trafficking kinetics or partner engagement, producing a functionally distinct isoform rather than a passive truncation.
Type: Isoform-resolved trafficking analysis
Experiment: Generate isogenic human astrocyte-neuron cocultures carrying representative stability- and localization-defective LRP10 variants, age the cultures, and measure APP/cargo traffic, extracellular-vesicle flux, and alpha-synuclein transfer at endogenous expression levels.
Hypothesis: Disease-associated loss of LRP10 perturbs a defined astrocytic cargo-sorting step that secondarily alters alpha-synuclein handling.
Type: Endogenous disease-variant mechanism study
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The physiological human cargo repertoire of LRP10, including whether it directly internalizes apoE-rich beta-VLDL in relevant human cell types, is unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: APP is a directly bound human cargo whose intracellular distribution depends on LRP10, whereas beta-VLDL uptake has been demonstrated only for mouse Lrp10 in a reconstituted cell system.
Significance: Defining endogenous cargos is necessary to distinguish the conserved sorting function of LRP10 from family-wide LDL-receptor assumptions.
What would resolve it: Quantitative endogenous cargo-binding and uptake assays in human astrocytes and other LRP10-expressing cells, coupled to LRP10 knockout and rescue, would establish cargo specificity and transport direction.
Provenance (the field's own admissions):
Gap: How SORL1 participates in LRP10-dependent sorting, and whether either receptor recruits the other or a shared trafficking complex, has not been established.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Endogenous LRP10 and SORL1 partially colocalize and interact in human astrocytes, but this observation does not demonstrate retromer membership or protein-macromolecule adaptor activity.
Significance: Resolving the interaction mechanism would explain how two sorting receptors coordinate cargo traffic in the human brain without overcalling complex membership.
What would resolve it: Endogenous reciprocal interaction mapping, acute depletion, and trafficking rescue with interface- and tail-motif mutants in human astrocytes would test directionality and dependence on retromer-associated machinery.
Provenance (the field's own admissions):
Gap: The cellular itinerary, cargo selectivity, and physiological consequences of LRP10 isoform 2 are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Isoform 2 lacks residues 557-713 of the cytoplasmic tail, but no direct isoform-specific localization or functional experiment is available.
Significance: The deletion removes much of the tail that could encode trafficking control, so treating isoform 2 as functionally equivalent to the full-length product is not yet justified.
What would resolve it: Endogenous isoform-specific tagging and knockout-rescue trafficking assays should compare APP sorting, SORL1 association, and organelle residence times.
Provenance (the field's own admissions):
Gap: The causal route from disease-associated LRP10 loss or mislocalization to Lewy-body disease phenotypes remains unresolved, and the reported alpha-synuclein effects have not been established as a universal normal function of LRP10.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Several disease-associated variants reduce RNA or protein stability or alter localization, while the available alpha-synuclein study used overexpression and model systems with acknowledged limitations.
Significance: Mechanistic resolution is required before disease association or extracellular vesicle observations can be promoted to a constitutive core function.
What would resolve it: Isogenic patient-variant knock-in models at endogenous abundance, evaluated in aged human astrocyte-neuron cocultures for cargo trafficking and alpha-synuclein handling, would test causality.
Provenance (the field's own admissions):
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