LRP2BP is a 347-residue cytoplasmic repeat protein containing one TPR and six Sel1-like repeats. It associates with a proline-rich region near the N terminus of the cytoplasmic tail of the multiligand receptor LRP2/megalin and has been proposed to recruit regulatory proteins to that tail. LRP2BP shows vesicular staining near the plasma membrane and throughout the cytoplasm. Its association with LRP2 did not block receptor endocytosis in the reported assay, and the downstream consequences for LRP2 trafficking or transcription remain unresolved. Two closely related splice isoforms are curated; isoform 2 carries a two-residue insertion after residue 35, but no isoform-specific function has been established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProtKB subcellular-location vocabulary mapping places LRP2BP in the cytoplasm. Reason: Cytoplasmic localization is consistent with LRP2BP acting as an intracellular receptor-tail adaptor and with the reviewed UniProtKB localization record. The broad compartment is appropriate and represents a core location. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: A BioPlex 2.0 affinity-purification mass-spectrometry screen reports an LRP2BP association with GSTT1. Reason: The curated IPI preserves a candidate co-association from a systematic proteome-scale screen, but generic protein binding does not describe a mechanistic molecular function of LRP2BP. The association should remain available as interaction provenance rather than be treated as a core GO function. Supporting Evidence: PMID:28514442 With more than 56,000 candidate interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The HuRI systematic binary-interactome screen reports LRP2BP interactions with eighteen human protein partners. Reason: These curator-assigned IPI records are retained as evidence for the reported binary pairs, including the specifically tested Q6NZ36-4 proteoform. They do not establish a shared mechanism for LRP2BP, so collapsing the screen into generic protein binding is functionally uninformative and should not be treated as core function. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: A BioPlex 3.0 affinity-purification mass-spectrometry screen reports an LRP2BP association with GSTT1. Reason: Recurrence of the LRP2BP-GSTT1 association in BioPlex 2.0 and 3.0 lends confidence to the reported co-association, but neither generic protein binding nor this screen result defines a mechanistic molecular function of LRP2BP. Preserve the interaction provenance as non-core screen evidence. Supporting Evidence: PMID:33961781 mass spectrometry, we have created two proteome-scale, cell-line-specific |
| GO:0005515 protein binding | IPI PMID:12508107 Functional interaction of megalin with the megalinbinding pr... | MODIFY | Summary: Yeast two-hybrid experiments identify LRP2BP/MegBP as a TPR-containing scaffold that binds the cytoplasmic tail of LRP2/megalin and additional protein partners. Reason: Direct binding to LRP2 is well supported, but generic protein binding is uninformative. The accessible evidence identifies LRP2BP as a scaffold and suggests that it recruits other proteins to the receptor tail, which is better represented by protein-macromolecule adaptor activity; the proposed downstream transcriptional model remains tentative. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:12508107 scaffold protein with tetratrico peptide repeats, the megalin-binding protein PMID:12508107 identified proteins that bound to MegBP and thus might be recruited to the megalin tail. MegBP-interacting partners included several transcriptional |
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Download this section (compressed HTML)Q: Which surface of human LRP2BP binds the proline-rich LRP2 tail, and does the interaction require a particular TPR or Sel1-like repeat?
Q: Which candidate LRP2BP partners form an endogenous complex with LRP2BP and LRP2, and can any partner bind simultaneously with the receptor tail?
Q: Does endogenous LRP2BP regulate cargo-specific LRP2 trafficking, receptor recycling, proteolysis, or transcriptional signaling in LRP2-expressing epithelia?
Q: Does the two-residue insertion in LRP2BP isoform 2 alter repeat packing, localization, partner choice, or LRP2 association?
Experiment: Reconstitute binding with purified human LRP2BP repeat fragments and the LRP2 cytoplasmic tail, then combine quantitative affinity measurements, systematic repeat mutagenesis, and structural analysis of the minimal complex.
Hypothesis: A defined subset of LRP2BP TPR/Sel1-like repeats recognizes the proline-rich N-terminal region of the LRP2 cytoplasmic tail.
Type: quantitative interaction mapping and structural analysis
Experiment: Endogenously tag LRP2BP and LRP2 in a human proximal-tubule or choroid-plexus epithelial model and use proximity labeling, reciprocal co-immunoprecipitation, and size-resolved native complex analysis before and after cargo uptake.
Hypothesis: LRP2BP assembles a regulated receptor-tail complex whose composition changes during the LRP2 endocytic cycle.
Type: endogenous receptor-complex proteomics
Experiment: Generate LRP2BP-null epithelial cells and rescue them with wild-type or LRP2-binding-defective LRP2BP, then quantify LRP2 surface abundance, cargo uptake, endosomal recycling, ectodomain shedding, and receptor-tail-dependent transcription.
Hypothesis: LRP2BP controls a subset of LRP2 trafficking or signaling outputs without being required for bulk receptor endocytosis.
Type: separation-of-function receptor trafficking analysis
Experiment: Express each LRP2BP isoform from the endogenous locus in otherwise isogenic cells and compare localization, LRP2-tail affinity, partner proteomes, and receptor functional outputs.
Hypothesis: The small isoform-2 insertion produces a measurable but context-dependent change in LRP2BP interaction specificity rather than a wholly distinct biological role.
Type: isoform-resolved endogenous complementation
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous molecular consequence of the LRP2BP-LRP2 association is unknown.
OPEN BIOLOGYCURATION BP_DARK
What is known: Targeted evidence establishes association with the LRP2 tail, but the reported interaction did not block receptor endocytosis, and the proposed transcriptional mechanism was not directly demonstrated.
Significance: Without a demonstrated output, no specific LRP2 trafficking or transcriptional biological-process term can be assigned to LRP2BP.
What would resolve it: Disrupt endogenous LRP2BP or its LRP2-binding interface in a physiological human epithelial model and measure cargo-specific receptor trafficking together with receptor-tail-dependent transcriptional outputs.
Provenance (the field's own admissions):
Gap: The LRP2BP-side interaction interface and endogenous complex composition are unresolved.
OPEN BIOLOGY MF_DARK
What is known: The study mapped a proline-rich binding region on LRP2 and recovered candidate LRP2BP partners, but no LRP2BP interface, stoichiometry, simultaneous ternary binding, or experimental structure has been established.
Significance: Defining the interface and complex is required to distinguish a physical receptor-tail scaffold from a broader constitutive adaptor mechanism.
What would resolve it: Map the minimal human LRP2BP-LRP2 interface structurally and determine endogenous complex composition and stoichiometry with orthogonal interaction assays.
Provenance (the field's own admissions):
Gap: The identity and dynamics of the LRP2BP-positive cytoplasmic vesicles are unknown.
OPEN BIOLOGY CC_DARK
What is known: The reviewed human record reports vesicular staining near the plasma membrane and throughout the cytoplasm, but no endosomal subtype, cargo state, or direct colocalization with LRP2 is resolved in the accessible evidence.
Significance: Compartment-resolved localization is needed before assigning a specific vesicle or endosomal cellular-component term.
What would resolve it: Endogenously tag LRP2BP and compare its dynamics with LRP2 and established endosomal markers during synchronized cargo uptake and receptor recycling.
Gap: The biological significance of LRP2BP isoform 2 is unknown.
OPEN BIOLOGY BP_DARK
What is known: UniProt curates a two-residue insertion after residue 35, but the targeted paper and interaction screens do not resolve which isoform was tested or establish an isoform-specific phenotype.
Significance: Isoform-resolved evidence is required before transferring canonical localization or adaptor function to a specific proteoform.
What would resolve it: Compare the two endogenous human isoforms in isogenic cells using quantitative localization, interaction, and LRP2 functional assays.
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