LRP4 is a 1,905-residue type-I cell-surface receptor with a large extracellular LDL-receptor-family repeat region, one transmembrane helix, and a cytoplasmic tail. At the neuromuscular junction, its ectodomain binds neuronal AGRIN and MuSK and assembles them into a signaling complex that activates MuSK and promotes acetylcholine-receptor clustering and synapse formation. In osteoblast-lineage cells, LRP4 directly binds the secreted inhibitor sclerostin and facilitates its suppression of canonical Wnt signaling and bone formation. Human variants that perturb different surfaces of the third beta-propeller selectively disrupt these neuromuscular or bone-regulatory functions, causing congenital myasthenic syndrome, Cenani-Lenz syndactyly syndrome, or sclerosteosis-like bone overgrowth.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA inference associates LRP4 with plasma membrane; exact ordered source provenance and any live annotation extensions are retained. Reason: Plasma-membrane localization is core to LRP4's type-I membrane coreceptor architecture and is independently consistent with the reviewed human record and human agrin-LRP4-MuSK structure. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0030706 SUPPORTS TRANSFER FB:FBgn0051092 SUPPORTS TRANSFER MGI:MGI:1340044 SUPPORTS TRANSFER MGI:MGI:1860083 SUPPORTS TRANSFER MGI:MGI:2138856 SUPPORTS TRANSFER MGI:MGI:2442252 SUPPORTS TRANSFER MGI:MGI:96765 SUPPORTS TRANSFER MGI:MGI:96828 SUPPORTS TRANSFER PANTHER:PTN002557696 SUPPORTS TRANSFER RGD:2998 SUPPORTS TRANSFER RGD:619731 SUPPORTS TRANSFER RGD:727887 SUPPORTS TRANSFER UniProtKB:E1BGJ0 SUPPORTS TRANSFER UniProtKB:P01130 SUPPORTS TRANSFER UniProtKB:P01131 SUPPORTS TRANSFER UniProtKB:P98155 SUPPORTS TRANSFER UniProtKB:Q07954 SUPPORTS TRANSFER UniProtKB:Q14114 SUPPORTS TRANSFER UniProtKB:Q86YD5 SUPPORTS TRANSFER UniProtKB:Q9NPF0 SUPPORTS TRANSFER UniProtKB:Q9Y561 SUPPORTS TRANSFER UniProtKB:Q9Y5Q5 SUPPORTS TRANSFER WB:WBGene00003071 SUPPORTS TRANSFER WB:WBGene00015083 SUPPORTS TRANSFER WB:WBGene00019811 SUPPORTS TRANSFER |
| GO:0048699 generation of neurons | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA inference associates LRP4 with generation of neurons; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000056094 SUPPORTS TRANSFER RGD:619731 SUPPORTS TRANSFER |
| GO:0050808 synapse organization | IBA GO_REF:0000033 | ACCEPT | Summary: IBA inference associates LRP4 with synapse organization; exact ordered source provenance and any live annotation extensions are retained. Reason: Synapse organization is a defining conserved LRP4 role, especially in neuromuscular-junction assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2442252 SUPPORTS TRANSFER PANTHER:PTN000056094 SUPPORTS TRANSFER RGD:619731 SUPPORTS TRANSFER |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA inference associates LRP4 with negative regulation of canonical Wnt signaling pathway; exact ordered source provenance and any live annotation extensions are retained. Reason: Negative regulation of canonical Wnt signaling is supported by direct human genetics and SOST-facilitator experiments as well as the curated phylogeny. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2442252 SUPPORTS TRANSFER PANTHER:PTN000056094 SUPPORTS TRANSFER UniProtKB:O75096 SUPPORTS TRANSFER Target self-WITH/FROM is expected IBA provenance and reflects target experimental grounding; it is not circular. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with calcium ion binding; exact ordered source provenance and any live annotation extensions are retained. Reason: The molecular property is compatible with LRP4 but is structural, generic, or ligand-contextual rather than the receptor's defining coreceptor activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR001881 SUPPORTS TRANSFER InterPro:IPR018097 SUPPORTS TRANSFER |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA inference associates LRP4 with plasma membrane; exact ordered source provenance and any live annotation extensions are retained. Reason: Plasma-membrane localization is core to LRP4's single-pass receptor architecture. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with symbiont entry into host cell; exact ordered source provenance and any live annotation extensions are retained. Reason: Yellow-fever-virus entry is experimentally supported for human LRP4, but pathogen exploitation is not the receptorβs core endogenous function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: GO:0001618 SOURCE WEAK OR INFERRED This logical-inference source is an ontology term, not a gene-level experimental donor. |
| GO:0048731 system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with system development; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027702 SOURCE WEAK OR INFERRED The ARBA rule is electronic provenance rather than direct experimental evidence. |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with animal gross anatomical part developmental process; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00098139 SOURCE WEAK OR INFERRED The ARBA rule is electronic provenance rather than direct experimental evidence. |
| GO:0005515 protein binding | IPI PMID:12421765 Protein-protein interactions between large proteins: two-hyb... | UNDECIDED | Summary: PMID:12421765 provides curator-assessed IPI evidence relating LRP4 to protein binding. Reason: The cached abstract describes a large-protein yeast-two-hybrid screen but does not identify the LRP4-WHRN pair or establish which WHRN domain binds. Under curator-deference rules the generic IPI annotation remains UNDECIDED. |
| GO:0005515 protein binding | IPI PMID:21471202 Bone overgrowth-associated mutations in the LRP4 gene impair... | MODIFY | Summary: PMID:21471202 provides curator-assessed IPI evidence relating LRP4 to protein binding. Reason: The direct LRP4-SOST interaction is informative, but generic protein binding obscures the demonstrated facilitator role. Current GO:0015026 coreceptor activity captures LRP4 cooperation in SOST-dependent inhibition of Wnt signaling. Proposed replacements: coreceptor activity Supporting Evidence: PMID:21471202 Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/Ξ²-catenin signaling. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: PMID:28514442 provides curator-assessed IPI evidence relating LRP4 to protein binding. Reason: The curator-made BioPlex IPI is retained as human AP-MS co-association evidence, and targeted PMID:21471202 independently supports LRP4-SOST binding. The screen row itself does not establish coreceptor activity, so generic binding remains non-core rather than being promoted to that functional term. Supporting Evidence: PMID:21471202 Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/Ξ²-catenin signaling. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: PMID:33961781 provides curator-assessed IPI evidence relating LRP4 to protein binding. Reason: The curator-made BioPlex IPI is retained as human AP-MS co-association evidence, and targeted PMID:21471202 independently supports LRP4-SOST binding. The screen row itself does not establish coreceptor activity, so generic binding remains non-core rather than being promoted to that functional term. Supporting Evidence: PMID:21471202 Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/Ξ²-catenin signaling. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: PMID:36115835 provides curator-assessed IPI evidence relating LRP4 to protein binding. Reason: This quantitative fragmentomics study measured interactions between the LRP4 C-terminal PDZ-binding motif and an ordered panel of PDZ-domain proteins. Current GO:0030165 PDZ domain binding captures the common mechanism more specifically than generic protein binding. Proposed replacements: PDZ domain binding |
| GO:0007167 enzyme-linked receptor protein signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with enzyme-linked receptor protein signaling pathway; exact ordered source provenance and any live annotation extensions are retained. Reason: LRP4 is an extracellular coreceptor for the MUSK receptor tyrosine kinase; this broad pathway term captures a core signaling role without assigning kinase activity to LRP4. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with cell surface; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0014069 postsynaptic density | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with postsynaptic density; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0015026 coreceptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with coreceptor activity; exact ordered source provenance and any live annotation extensions are retained. Reason: Coreceptor activity is a defining molecular role of LRP4 in the AGRIN-LRP4-MUSK signaling complex and in SOST-dependent Wnt inhibition. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0030425 dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with dendrite; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0030971 receptor tyrosine kinase binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA inference associates LRP4 with receptor tyrosine kinase binding; exact ordered source provenance and any live annotation extensions are retained. Reason: Binding the receptor tyrosine kinase MUSK is a defining molecular interaction in LRP4-dependent neuromuscular-junction assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0031594 neuromuscular junction | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with neuromuscular junction; exact ordered source provenance and any live annotation extensions are retained. Reason: The neuromuscular junction is a defining site of LRP4 action. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0034185 apolipoprotein binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA inference associates LRP4 with apolipoprotein binding; exact ordered source provenance and any live annotation extensions are retained. Reason: This electronic transfer traces only to inferred rat Lrp4 records and no primary rat or human LRP4 apolipoprotein-binding evidence was identified. The LDL-receptor-family fold does not establish the multiligand lipoprotein-binding repertoire of LRP1 or LRP2 in LRP4. Propagation Review Root cause: PROPAGATION BAD Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q9QYP1 SOURCE WEAK OR INFERRED ensembl:ENSRNOP00000021353 SOURCE WEAK OR INFERRED |
| GO:0035022 positive regulation of Rac protein signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with positive regulation of Rac protein signal transduction; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA inference associates LRP4 with protein homodimerization activity; exact ordered source provenance and any live annotation extensions are retained. Reason: The reviewed human record only transfers a nonspecific homooligomer statement by similarity, and the electronic rat sources do not establish a dimer stoichiometry or a dimer-specific molecular activity for human LRP4. The term is therefore more specific than the accessible evidence. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8VI56 SOURCE WEAK OR INFERRED ensembl:ENSMUSP00000028689 SOURCE WEAK OR INFERRED |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with neuronal cell body; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0044853 plasma membrane raft | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with plasma membrane raft; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0045202 synapse | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with synapse; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0048813 dendrite morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with dendrite morphogenesis; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0050771 negative regulation of axonogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with negative regulation of axonogenesis; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0050808 synapse organization | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with synapse organization; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0051124 synaptic assembly at neuromuscular junction | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with synaptic assembly at neuromuscular junction; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0071340 skeletal muscle acetylcholine-gated channel clustering | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with skeletal muscle acetylcholine-gated channel clustering; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0097060 synaptic membrane | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with synaptic membrane; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0097104 postsynaptic membrane assembly | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with postsynaptic membrane assembly; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0097105 presynaptic membrane assembly | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with presynaptic membrane assembly; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0097110 scaffold protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP4 with scaffold protein binding; exact ordered source provenance and any live annotation extensions are retained. Reason: Scaffold-protein binding is plausible in neuronal LRP4 biology but is secondary to its core extracellular coreceptor activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER ensembl:ENSRNOP00000021353 SUPPORTS TRANSFER |
| GO:0150052 regulation of postsynapse assembly | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with regulation of postsynapse assembly; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:1901631 positive regulation of presynaptic membrane organization | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with positive regulation of presynaptic membrane organization; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:1904395 positive regulation of skeletal muscle acetylcholine-gated channel clustering | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP4 with positive regulation of skeletal muscle acetylcholine-gated channel clustering; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER ensembl:ENSMUSP00000028689 SUPPORTS TRANSFER |
| GO:0001618 virus receptor activity | IMP PMID:41162706 Multiple LDLRΒ family members act as entry receptors for yell... | KEEP AS NON CORE | Summary: PMID:41162706 provides curator-assessed IMP evidence relating LRP4 to virus receptor activity. Reason: The 2026 study directly establishes LRP4-dependent yellow-fever-virus entry, but this is pathogen exploitation rather than an endogenous core function. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with plasma membrane; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0150094 amyloid-beta clearance by cellular catabolic process | IMP PMID:18289866 LRP promotes endocytosis and degradation, but not transcytos... | REMOVE | Summary: PMID:18289866 provides curator-assessed IMP evidence relating LRP4 to amyloid-beta clearance by cellular catabolic process. Reason: The paper explicitly defines βmLRP4β as an LRP mini-receptor in an LRP amyloid-beta experiment; it does not study the LRP4 gene product O75096. This is a verified homonym/construct misattribution. Supporting Evidence: PMID:18289866 MDCK cells were stably transfected with Pgp or mLRP4, an LRP mini-receptor. |
| GO:0044853 plasma membrane raft | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP4 with plasma membrane raft; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0009986 cell surface | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with cell surface; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0014069 postsynaptic density | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP4 with postsynaptic density; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0030971 receptor tyrosine kinase binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with receptor tyrosine kinase binding; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0031594 neuromuscular junction | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with neuromuscular junction; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0051124 synaptic assembly at neuromuscular junction | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with synaptic assembly at neuromuscular junction; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0097110 scaffold protein binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP4 with scaffold protein binding; exact ordered source provenance and any live annotation extensions are retained. Reason: The molecular property is compatible with LRP4 but is structural, generic, or ligand-contextual rather than the receptor's defining coreceptor activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0030425 dendrite | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP4 with dendrite; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0043025 neuronal cell body | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP4 with neuronal cell body; exact ordered source provenance and any live annotation extensions are retained. Reason: This localization is biologically compatible but is a secondary neuronal subcompartment or broad contextual location rather than the defining plasma-membrane/neuromuscular-junction site. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0097060 synaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with synaptic membrane; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0050771 negative regulation of axonogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP4 with negative regulation of axonogenesis; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0048813 dendrite morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP4 with dendrite morphogenesis; exact ordered source provenance and any live annotation extensions are retained. Reason: This is a broad developmental, neuronal, cargo-specific, or downstream context rather than LRP4's core molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0050808 synapse organization | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with synapse organization; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9QYP1 SUPPORTS TRANSFER |
| GO:0071340 skeletal muscle acetylcholine-gated channel clustering | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with skeletal muscle acetylcholine-gated channel clustering; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0097104 postsynaptic membrane assembly | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with postsynaptic membrane assembly; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0097105 presynaptic membrane assembly | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with presynaptic membrane assembly; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0001822 kidney development | IDA PMID:20381006 LRP4 mutations alter Wnt/beta-catenin signaling and cause li... | KEEP AS NON CORE | Summary: PMID:20381006 provides curator-assessed IDA evidence relating LRP4 to kidney development. Reason: Human recessive LRP4 variants establish a developmental requirement associated with kidney malformations; this organismal phenotype is important but non-core relative to the receptorβs molecular role. |
| GO:0009986 cell surface | IDA PMID:20381006 LRP4 mutations alter Wnt/beta-catenin signaling and cause li... | ACCEPT | Summary: PMID:20381006 provides curator-assessed IDA evidence relating LRP4 to cell surface. Reason: Cell-surface localization is consistent with LRP4's experimentally established type-I membrane topology and receptor functions; curator evidence is accepted despite the abstract not detailing the localization assay. |
| GO:0060173 limb development | IDA PMID:20381006 LRP4 mutations alter Wnt/beta-catenin signaling and cause li... | KEEP AS NON CORE | Summary: PMID:20381006 provides curator-assessed IDA evidence relating LRP4 to limb development. Reason: Human LRP4 variants establish an essential role in limb development, but this pleiotropic developmental outcome is non-core. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IMP PMID:20381006 LRP4 mutations alter Wnt/beta-catenin signaling and cause li... | ACCEPT | Summary: PMID:20381006 provides curator-assessed IMP evidence relating LRP4 to negative regulation of canonical Wnt signaling pathway. Reason: The human genetics study explicitly states that LRP4 antagonizes LRP6-mediated canonical Wnt activation and that patient mutations lose this function. |
| GO:1901631 positive regulation of presynaptic membrane organization | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP4 with positive regulation of presynaptic membrane organization; exact ordered source provenance and any live annotation extensions are retained. Reason: The annotation is consistent with LRP4's conserved core role as a cell-surface organizer/coreceptor for AGRIN-MUSK signaling and synapse assembly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VI56 SUPPORTS TRANSFER |
| GO:0030279 negative regulation of ossification | IMP PMID:21471202 Bone overgrowth-associated mutations in the LRP4 gene impair... | KEEP AS NON CORE | Summary: PMID:21471202 provides curator-assessed IMP evidence relating LRP4 to negative regulation of ossification. Reason: The SOST-facilitator study supports inhibition of bone mineralization/ossification, but this tissue-level output is non-core. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IMP PMID:21471202 Bone overgrowth-associated mutations in the LRP4 gene impair... | ACCEPT | Summary: PMID:21471202 provides curator-assessed IMP evidence relating LRP4 to negative regulation of canonical Wnt signaling pathway. Reason: Direct interaction, perturbation, and disease-variant evidence support LRP4-mediated negative regulation of canonical Wnt signaling. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IDA PMID:20093106 The low-density lipoprotein receptor-related protein 10 is a... | ACCEPT | Summary: PMID:20093106 provides curator-assessed IDA evidence relating LRP4 to negative regulation of canonical Wnt signaling pathway. Reason: The cached abstract explicitly centers the distinct LRP10 protein and does not expose the LRP4 experiment seen by the curator. Nevertheless, direct human genetic and perturbation evidence in PMID:20381006 and PMID:21471202 independently establishes this exact LRP4 function, so the term is accepted while retaining the citation caveat rather than overruling the curator. Supporting Evidence: PMID:20093106 Here, we found that LRP10, a new member of the LDLR gene family, inhibits the canonical Wnt/beta-catenin signaling pathway. PMID:20381006 By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS. LRP4 belongs to the low-density lipoprotein (LDL) receptor-related proteins (LRPs), which are essential for various developmental processes. LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: How does full-length membrane-embedded human LRP4 couple the extracellular AGRIN-LRP4-MuSK assembly to MuSK activation and synaptic organization?
Q: How do distinct surfaces of LRP4 beta-propeller 3 select AGRIN/MuSK versus sclerostin/Wnt pathway partners in different tissues?
Q: Which PDZ-domain proteins bind the full-length LRP4 cytoplasmic tail endogenously, and do any regulate neuromuscular or bone signaling?
Q: Does human LRP4 directly facilitate DKK1 signaling in osteoblasts, or is its established human Wnt-inhibitory role specific to sclerostin?
Q: Does LRP4 undergo regulated cleavage, endocytosis, or recycling that changes the balance between its AGRIN/MuSK and sclerostin/Wnt functions?
Experiment: Endogenously tag LRP4 and MuSK in human myotubes and combine ligand-timed single-molecule imaging, phosphoproteomics, and AChR-clustering assays with rescue by interface-specific LRP4 variants.
Hypothesis: AGRIN stabilizes a full-length LRP4-MuSK assembly whose geometry, rather than an intrinsic LRP4 catalytic activity, drives MuSK activation and AChR clustering.
Type: endogenous neuromuscular receptor-complex analysis
Experiment: Determine a membrane-context structure of full-length human LRP4 with AGRIN and MuSK by cryo-electron tomography or single-particle cryo-EM, including the transmembrane segments and cytoplasmic tails.
Hypothesis: Membrane anchoring and unresolved LRP4 regions impose additional geometry on the AGRIN-LRP4-MuSK complex that is absent from the soluble 21-1350 ectodomain structure.
Type: full-length membrane-protein structural analysis
Experiment: Introduce pathway-selective third-propeller variants into isogenic human osteoblasts and myotubes, then compare sclerostin/Wnt inhibition, AGRIN/MuSK activation, and receptor surface abundance.
Hypothesis: Spatially distinct third-propeller surfaces independently encode LRP4's bone and neuromuscular functions rather than causing a shared folding defect.
Type: separation-of-function variant analysis
Experiment: Validate candidate PDZ-tail partners by endogenous co-immunoprecipitation and proximity labeling in human myotubes and osteoblasts, followed by partner knockout and rescue assays in each signaling context.
Hypothesis: Only a subset of peptide-binding PDZ proteins forms physiological LRP4 complexes, with tissue-specific effects on receptor localization or signaling.
Type: endogenous cytoplasmic-tail interactome validation
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The architecture and signaling behavior of full-length membrane-embedded human LRP4 in the AGRIN-LRP4-MuSK complex remain unresolved.
OPEN BIOLOGY MF_DARK
What is known: The human cryo-EM study used LRP4 residues 21-1350, and substantial extracellular regions, the transmembrane helix, and the entire cytoplasmic tail are absent or unresolved. It establishes extracellular partner recruitment, not the complete receptor activation mechanism.
Significance: A full-length structure is needed to connect extracellular coreceptor assembly to membrane organization and intracellular MuSK activation.
What would resolve it: Resolve a membrane-context full-length human AGRIN-LRP4-MuSK complex and test structural predictions with interface-selective rescue assays.
Provenance (the field's own admissions):
Gap: Direct endogenous human-neuromuscular evidence for LRP4 complex dynamics and signaling is limited.
OPEN BIOLOGY BP_DARK
What is known: Foundational functional experiments use mammalian cell lines and mouse muscle, while human evidence comes from a soluble-fragment structure and disease variants. These sources strongly support conserved mechanism but do not directly visualize full-length LRP4 signaling at a human neuromuscular junction.
Significance: Human endogenous measurements are needed to define complex lifetime, pathway stoichiometry, and variant effects in the native synaptic context.
What would resolve it: Use patient-derived or engineered human neuromuscular cocultures for endogenous complex imaging, MuSK phosphosignaling, and AChR-clustering rescue.
Gap: The molecular basis for pathway-selective effects of LRP4 beta-propeller variants is incomplete.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human variants and mutagenesis distinguish a MuSK-regulating edge from a Wnt-regulating central cavity, but folding, trafficking, partner occupancy, and tissue-specific effects have not been compared in one system.
Significance: Resolving this distinction is essential for interpreting disease variants without assuming that every allele disrupts both core pathways.
What would resolve it: Compare surface expression, structure, AGRIN/MuSK binding, sclerostin binding, and downstream signaling for a systematic variant panel in matched human cell models.
Provenance (the field's own admissions):
Gap: The physiological LRP4 cytoplasmic-tail interactome and its contribution to either core pathway are unknown.
OPEN BIOLOGY MF_DARK
What is known: Fragmentomics supports PDZ-domain binding by an LRP4 tail peptide, but the assay does not establish that every partner binds full-length LRP4 in cells or regulates neuromuscular or bone signaling.
Significance: Partner validation is required before assigning specific scaffold complexes or downstream tail-mediated processes to LRP4.
What would resolve it: Test endogenous full-length LRP4 complexes and partner-specific functional effects in human myotubes and osteoblasts.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)