LRP1B is a very large type-I single-pass cell-surface member of the LDL-receptor family, with an extracellular repeat-rich ligand-binding region and a short cytoplasmic tail containing two endocytic NPxY motifs. Human LRP1B minireceptors bind, internalize, and degrade selected protease and protease-inhibitor ligands and also internalize VLDL; recombinant ectodomains bind fibrinogen and apoE-bearing lipoproteins. LRP1B minireceptors also bind selected APP forms and alter APP processing. Internalization is markedly slower than for LRP1, prolonging cargo residence at the cell surface. In cultured human non-small-cell lung cancer cells, depletion of endogenous LRP1B increases proliferation, whereas expression of full-length mouse Lrp1b or a human LRP1B minireceptor suppresses growth. The responsible cargo and in-vivo mechanism remain unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as the core cell-surface location of this single-pass type-I membrane receptor. The ordered IBA sources exactly match current QuickGO and the local GOA. Reason: Reviewed human Q9NZR2 has a signal peptide, a large extracellular region, one transmembrane helix, and a cytoplasmic tail, while UniProt classifies it as a membrane receptor. Although the IBA donor set spans LDL-receptor-family paralogs, plasma-membrane activity is compatible with this conserved topology and with LRP1B's ligand-internalization role. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0261260 · Drosophila mgl SUPPORTS TRANSFER Exact WITH/FROM source; conserved cell-surface receptor topology supports plasma-membrane activity despite the evolutionary distance. MGI:MGI:95794 · mouse Lrp2 SUPPORTS TRANSFER Exact WITH/FROM paralog source; the shared single-pass LDL-receptor-family topology supports this broad location. PANTHER:PTN008580766 · PANTHER LDL-receptor-family node SUPPORTS TRANSFER Exact phylogenetic node; its broad family scope is acceptable for conserved membrane topology but not evidence for LRP1B-specific ligand specificity. RGD:68407 · rat Lrp2 SUPPORTS TRANSFER Exact WITH/FROM paralog source; it supports the conserved cell-surface receptor location. UniProtKB:P98164 · human LRP2 SUPPORTS TRANSFER Exact WITH/FROM paralog source; its homologous receptor topology supports the plasma-membrane assignment. |
| GO:0005041 low-density lipoprotein particle receptor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retained as a direct-ortholog LDL-particle receptor inference, but marked non-core because human target experiments directly establish VLDL rather than LDL uptake. Reason: The experimental donor is the direct mouse Lrp1b ortholog, and no evidence here demonstrates target-specific loss or invalid node placement. The IBA is therefore retained rather than replaced. It remains non-core because GO:0005041 requires LDL-particle binding and uptake, whereas direct human target evidence currently establishes the distinct VLDL activity represented by the separate NEW row. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:2151136 · mouse Lrp1b SUPPORTS TRANSFER Exact direct-ortholog WITH/FROM source; there is no target-specific divergence evidence that would invalidate the PAINT transfer, although direct human LDL uptake has not been assayed in the cited target literature. PANTHER:PTN008580767 · PANTHER phylogenetic node SOURCE WEAK OR INFERRED Exact inference node retained for provenance. It is not treated as independent experimental evidence or as proof that the broader family is LRP1B-specific. |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | UNDECIDED | Summary: Undecided because the current term requires membership in a signaling receptor complex, whereas the traceable evidence concerns broad LDL-receptor-family and PX-FERM cargo biology rather than an explicit LRP1B signaling complex. Reason: Current GO:0043235 is not merely a receptor label: it denotes a protein complex that binds a signaling molecule to initiate a change in cell function. The IBA source set is dominated by LRP2 paralogs, a broad PANTHER node, and the human target itself. PMID:23382219 is accessible but contains no explicit LRP1B passage in the cached body and describes many screened proteins as putative PX-FERM cargos. Curator deference therefore favors UNDECIDED rather than removal. Propagation Review Root cause: UNRESOLVED Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH SOURCE EVIDENCE WEAK Sources checked: PANTHER:PTN008580766 · PANTHER LDL-receptor-family node SOURCE WEAK OR INFERRED Exact node, but its mixed LDL-receptor-family scope does not independently establish an LRP1B-containing signaling receptor complex. RGD:68407 · rat Lrp2 SUPPORTS SOURCE BUT NOT TARGET Exact paralog donor; LRP2 complex evidence does not by itself license complex membership for human LRP1B. UniProtKB:P98164 · human LRP2 SUPPORTS SOURCE BUT NOT TARGET Exact paralog donor with its own PMID:23382219 annotation; transfer across LRP2 and LRP1B remains unsafe for this complex-level term. UniProtKB:Q9NZR2 · human LRP1B SOURCE WEAK OR INFERRED Exact target self-source expected in the IBA WITH/FROM structure. It is retained as valid provenance but is not an independent experimental donor; the concern instead rests on the mixed LRP2-family sources and current complex-term scope. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Retained as a correct but non-core domain-level molecular function of the large extracellular LDL-receptor-family region. Reason: Reviewed Q9NZR2 contains many LDL-receptor class-A modules and explicitly calcium-binding EGF-like domains. The ordered InterPro mappings are therefore structurally appropriate, but calcium binding is ancillary to the defining receptor and endocytic role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR001881 · EGF-like calcium-binding domain SUPPORTS TRANSFER Exact InterPro source; the corresponding calcium-binding module is present in reviewed Q9NZR2. InterPro:IPR018097 · EGF-like calcium-binding conserved site SUPPORTS TRANSFER Exact InterPro source; the conserved site mapping supports calcium-ion binding without implying a catalytic calcium-dependent activity. |
| GO:0006898 receptor-mediated endocytosis | IEA GO_REF:0000117 | ACCEPT | Summary: Accepted as the core biological process predicted by the ARBA model and supported independently by LRP1B receptor architecture and ligand internalization biology. Reason: LRP1B is a single-pass surface receptor with two predicted cytoplasmic endocytosis motifs, and reviewed UniProt states that bound extracellular ligands are internalized and degraded. The electronic model is therefore consistent with the human protein rather than an autonomous enzyme or signaling activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00044584 · ARBA receptor-mediated-endocytosis model SOURCE WEAK OR INFERRED Exact electronic source. It is not independent experimental evidence, but its prediction agrees with reviewed LRP1B topology and ligand internalization. Supporting Evidence: PMID:11384978 Ligands of LRP including receptor-associated protein, urokinase plasminogen activator, tissue-type plasminogen activator, and plasminogen activator inhibitor type-1 each demonstrate binding, internalization, and degradation via mLRP1B4. |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retained as a correct but non-core conservative localization mapped from the reviewed UniProt membrane record. Reason: Q9NZR2 has a signal peptide, extracellular ectodomain, single transmembrane helix, and cytoplasmic tail. GO:0016020 is accurate but generic and is superseded as a core location by the more informative plasma-membrane annotation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0162 · UniProtKB membrane subcellular-location vocabulary SUPPORTS TRANSFER Exact mapping source; the reviewed Q9NZR2 transmembrane topology directly supports membrane localization. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Marked over-annotated: this normalized row records systematic yeast-two-hybrid candidate interactions with APP, CHRNA4, and PPP2R2A but assigns only the uninformative generic binding term. Reason: PMID:32814053 is a proteome-scale interaction screen, and its abstract does not provide LRP1B-specific orthogonal validation or a functional consequence for the three pairs. APP does have separate targeted minireceptor evidence in PMID:15126508, which is represented in the core synthesis; it does not rescue this screen-derived generic binding assertion or license a more specific APP activity term without a precise supported GO fit. CHRNA4 and PPP2R2A remain screen-only. Supporting Evidence: PMID:32814053 candidate interactions and is generated by systematic yeast two-hybrid |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | UNDECIDED | Summary: Undecided because the cached full text does not explicitly identify LRP1B, and the study's broad PX-FERM cargo screen does not clearly establish membership in a signaling receptor complex under the current GO definition. Reason: The curator may have used supplementary peptide-array data not represented in the extracted body, so the experimental annotation is not removed. However, PMID:23382219 frames many newly screened proteins as putative trafficking cargos, whereas GO:0043235 requires a complex that binds a signaling molecule and initiates a change in cell function. Available evidence cannot resolve that mismatch. Supporting Evidence: PMID:23382219 Although the possibility remains to be confirmed, these results strongly suggest that PX-FERM proteins are involved in the transport of these proteins within the endosomal system. |
| GO:0006898 receptor-mediated endocytosis | TAS PMID:10766186 LRP-DIT, a putative endocytic receptor gene, is frequently i... | ACCEPT | Summary: Accepted as the specific biological process stated for the predicted LRP1B receptor and corroborated by its conserved receptor architecture. Reason: PMID:10766186 is abstract-only and describes LRP1B as putative, but explicitly relates the 4599-residue product to the LRP1 endocytic receptor. TAS appropriately captures that traceable author statement without pretending it is a direct assay; reviewed UniProt independently records ligand internalization. Supporting Evidence: PMID:10766186 The predicted LRP-DIT product of 4599 amino acids has extensive homology to a gigantic receptor, LRP1, which mediates endocytosis of multiple proteins from the cell surface. |
| GO:0015031 protein transport | TAS PMID:10766186 LRP-DIT, a putative endocytic receptor gene, is frequently i... | MODIFY | Summary: Modified because the cited author statement specifically concerns receptor-mediated internalization of extracellular protein ligands, not generic protein transport. Reason: GO:0015031 is too broad and can imply many unrelated protein-trafficking processes. PMID:10766186 instead points to uptake of proteins from the cell surface by an LRP1- like receptor, which is captured precisely by GO:0006898 receptor-mediated endocytosis and is already independently represented for LRP1B. Proposed replacements: receptor-mediated endocytosis Supporting Evidence: PMID:10766186 The predicted LRP-DIT product of 4599 amino acids has extensive homology to a gigantic receptor, LRP1, which mediates endocytosis of multiple proteins from the cell surface. |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:27626682 Expression of a recombinant full-length LRP1B receptor in hu... | NEW | Summary: Proposed direct human annotation for the growth-suppressive effect of endogenous LRP1B in cultured non-small-cell lung cancer cells. Reason: siRNA depletion of endogenous human LRP1B increased Calu-1 proliferation, while reciprocal expression experiments with full-length mouse Lrp1b or a human LRP1B minireceptor reduced proliferation in other human NSCLC lines. GO:0008285 captures the experimentally observed direction without asserting an in-vivo tumor- suppressor mechanism or identifying an untested downstream pathway. Supporting Evidence: PMID:27626682 Conversely, in Calu-1 cells, which express higher endogenous levels of the receptor, siRNA-mediated LRP1B knockdown significantly enhanced cellular proliferation. |
| GO:0030229 very-low-density lipoprotein particle receptor activity | IDA PMID:21420681 LRP1b shows restricted expression in human tissues and binds... | NEW | Summary: Proposed direct human annotation for VLDL binding and internalization by an LRP1B region-IV minireceptor. Reason: GO:0030229 exactly describes combining with VLDL and delivering it into the cell through endocytosis. PMID:21420681 demonstrates both steps using a human LRP1B minireceptor in cultured cells. The annotation is confined to VLDL and does not imply LDL-particle uptake, systemic plasma clearance, or behavior of every ligand. Supporting Evidence: PMID:21420681 Furthermore, binding as well as internalization of very low density lipoproteins by cells expressing an LRP1b minireceptor was demonstrated. |
| GO:0038024 cargo receptor activity | IDA PMID:11384978 The putative tumor suppressor LRP1B, a novel member of the l... | NEW | Summary: Proposed direct human annotation for LRP1B's multiligand cargo-receptor activity. Reason: A human LRP1B region-IV minireceptor binds, internalizes, and degrades multiple extracellular protein cargos, while independent cytoplasmic-tail experiments show NPxY-dependent recognition by endocytic adaptors. Together these results fit the current cargo-receptor definition without assigning an autonomous signaling or catalytic activity. The minireceptor boundary and unresolved endogenous full- length cargo repertoire remain explicit. Supporting Evidence: PMID:11384978 Ligands of LRP including receptor-associated protein, urokinase plasminogen activator, tissue-type plasminogen activator, and plasminogen activator inhibitor type-1 each demonstrate binding, internalization, and degradation via mLRP1B4. PMID:17658514 From these data, we propose that both halves of the LRP1B cytoplasmic tail contribute to a unique global conformation, which results in less efficient recognition by endocytic adaptors and a slow endocytosis rate. |
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Download this section (compressed HTML)Q: Which endogenous ligands and cytoplasmic adaptors control full-length human LRP1B internalization in each expressing tissue?
Suggested experts: Endocytic trafficking experts, LDL-receptor-family biologists
Q: Does LRP1B have a physiologically important lipoprotein-uptake role in brain, thyroid, or skeletal muscle despite its restricted expression?
Suggested experts: Lipoprotein metabolism experts, Tissue physiologists
Q: Which cargo-retention or signaling change mediates LRP1B-dependent suppression of NSCLC-cell proliferation?
Suggested experts: Cancer cell biologists, Surface-proteome experts
Q: Is endogenous human LRP1B proteolytically processed or incorporated into a stable signaling complex in any native cell type?
Suggested experts: Receptor biochemists, Structural biologists
Q: Are any human LRP1B splice transcripts translated into stable receptors with distinct ligand or trafficking properties?
Suggested experts: Long-read transcriptomics experts, Proteogenomics experts
Experiment: Endogenously tag LRP1B in a naturally expressing human cell model, introduce single- and double-NPxY mutations, and quantify adaptor occupancy, surface half- life, and ligand uptake alongside matched LRP1 controls.
Hypothesis: Full-length human LRP1B uses both NPxY motifs to recruit endocytic adaptors but internalizes selected cargo more slowly than LRP1.
Type: endogenous receptor trafficking and motif mutagenesis
Experiment: Compare LRP1B-dependent uptake of defined lipoprotein particles in human brain, thyroid, and skeletal-muscle organoid models using knockout/rescue and quantitative lipid tracing.
Hypothesis: Tissue-restricted LRP1B mediates selective apoE-lipoprotein uptake rather than bulk systemic lipoprotein clearance.
Type: tissue-resolved ligand uptake
Experiment: Perform surface proteomics and uptake profiling after endogenous LRP1B knockout and rescue, nominate altered cargos, and test whether cargo-specific perturbation reproduces or reverses the proliferation phenotype.
Hypothesis: LRP1B suppresses NSCLC proliferation by retaining a specific growth-regulatory cargo at the plasma membrane.
Type: causal surface-proteome perturbation
Experiment: Analyze endogenous receptor maturation by pulse-chase labeling, N-terminomics, native mass spectrometry, and crosslinking in multiple human cell types, with LRP1 as a processing and complex-assembly comparator.
Hypothesis: Human full-length LRP1B remains an uncleaved single-chain receptor and does not form an obligate signaling complex.
Type: receptor processing and native-complex analysis
Experiment: Combine tissue long-read sequencing, targeted junction proteomics, and isoform- specific rescue assays measuring plasma-membrane delivery and ligand uptake.
Hypothesis: Predicted human LRP1B splice transcripts do not produce stable, functionally distinct receptor isoforms.
Type: isoform-resolved transcript and protein analysis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous full-length human LRP1B ligand repertoire, adaptor usage, and tissue-specific internalization kinetics are not established.
OPEN BIOLOGY MF_DARK
Significance: Most mechanistic assays used a region-IV minireceptor, while the intact receptor is 4,599 residues and may impose different ligand accessibility, processing, and trafficking constraints.
What would resolve it: Endogenously tag LRP1B in naturally expressing human cells, quantify uptake of candidate ligands, map cytoplasmic-tail adaptor occupancy, and compare results with matched full-length and minireceptor rescue constructs.
Provenance (the field's own admissions):
Gap: The normal physiological roles of LRP1B in its restricted human tissue-expression domains, including the importance of lipoprotein uptake, remain unresolved.
OPEN BIOLOGY BP_DARK
Significance: Recombinant ectodomains and minireceptors bind apoE-bearing lipoproteins and VLDL, but restricted expression argues against simply assigning the systemic clearance role of LRP1 to LRP1B.
What would resolve it: Measure endogenous LRP1B-dependent cargo uptake and extracellular proteome changes in human brain, thyroid, and skeletal-muscle models, then test tissue-selective loss-of-function in vivo.
Provenance (the field's own admissions):
Gap: The molecular connection between LRP1B cargo trafficking and suppression of cancer-cell proliferation is unknown.
OPEN BIOLOGY BP_DARK
Significance: Direct perturbation supports a growth-suppressive effect in cultured NSCLC cells, but no cargo, adaptor, or downstream pathway has been shown to cause that effect, and in-vivo human tumor suppression has not been tested experimentally.
What would resolve it: Combine endogenous LRP1B knockout and rescue with surface proteomics, cargo uptake, phosphoproteomics, and proliferation assays, then validate the causal cargo or pathway in patient-derived tumor models.
Provenance (the field's own admissions):
Gap: Full-length human LRP1B processing, higher-order structure, and possible stable receptor-complex membership are unresolved.
OPEN BIOLOGY CC_DARK
Significance: No experimental full-length structure or LRP1B-containing receptor complex is available, and mouse evidence that Lrp1b remains a single polypeptide cannot define human processing or complex stoichiometry.
What would resolve it: Characterize endogenous human LRP1B maturation and oligomeric state by pulse-chase proteomics, native complex analysis, and cryo-electron tomography or fragment- guided structural methods in a native membrane context.
Provenance (the field's own admissions):
Gap: Whether human LRP1B produces functional alternative protein isoforms is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
Significance: Mouse splice-form evidence and a predicted human exon-skipping transcript have not yielded a reviewed human alternative product or an experimentally validated human protein isoform.
What would resolve it: Use long-read RNA sequencing and junction-specific proteomics across LRP1B- expressing human tissues, followed by isoform-resolved ligand-uptake assays for any reproducibly detected protein products.
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