LRP8 (ApoER2) is the reviewed human Q14114 record and is 963 amino acids long [file:human/LRP8/LRP8-uniprot.txt "ID LRP8_HUMAN Reviewed; 963 AA."]. The record describes a single-pass type-I membrane receptor with an extracellular N-terminal region and a cytoplasmic tail; it annotates seven LDL-receptor class A repeats [file:human/LRP8/LRP8-uniprot.txt "DR Pfam; PF00057; Ldl_recept_a; 7."]. This is ApoER2/LRP8, not LRP1, LRP2, LRP4, LRP5, LRP6, LDLR, or VLDLR; family-level transfers must therefore be limited to functions demonstrably conserved in LRP8.
The UniProt record lists five named isoforms [file:human/LRP8/LRP8-uniprot.txt "CC Event=Alternative splicing; Named isoforms=5;"]. Isoform 2 combines changes affecting residues 166-295, the O-glycan-rich region, and residues 893-951; isoform 3 shares the 893-951 deletion, whereas isoform 4 has a distinct change and deletion spanning the LDLRA4-7 region. Isoform 5 has no sequence described in the current record. These are tested-product boundaries, not evidence that every reported LRP8 function is isoform-specific. Human tissue work independently found splice forms affecting three ligand-binding repeats, an EGF-precursor repeat, the O-glycosylation region, or the cytoplasmic domain PMID:10218790. In human platelets, the major transcript lacked repeats 4-6 but retained the full cytoplasmic tail PMID:10508213.
The earliest human receptor study showed that human ApoER2 expressed in LDLR-deficient CHO cells bound and internalized apoE-rich beta-migrating VLDL PMID:8626535. Later transfected-cell assays measured specific binding of phospholipid-associated apoE particles to ApoER2 PMID:12950167. These establish ligand-binding and uptake capability, while the heterologous systems limit claims about endogenous human tissue physiology.
Reelin binds directly to ApoER2 and VLDLR PMID:10571240. Surface plasmon resonance found greater ApoER2 affinity for Reelin than VLDLR PMID:12899622. Structural evidence is restricted to the ApoER2 LA1 module complexed with a Reelin fragment, not full-length LRP8 PMID:20223215. The classic neuronal-layering phenotype is mouse double-knockout evidence: loss of both VLDLR and ApoER2 phenocopied Reelin/Dab1 deficiency PMID:10380922. It should not be rewritten as a human LRP8-only phenotype.
Other direct, context-specific ligand evidence includes platelet beta2-glycoprotein I PMID:12807892, activated protein C signaling in human U937 cells PMID:19116273, and clusterin binding/internalization PMID:24381170. “APC” in PMID:19116273 is activated protein C, not the APC tumor-suppressor protein. Platelet, monocytic-cell, and proposed neurogenic effects remain non-core contexts unless stronger breadth evidence emerges.
PCSK9 can drive ApoER2 degradation following co-expression or re-internalization of secreted human PCSK9 PMID:18039658. IDOL directly targets the receptor cytoplasmic tail for ubiquitination and degradation PMID:20427281. In HEK293 experiments using murine receptor constructs, full-length Reelin reorganized preformed receptor oligomers into higher-order clusters PMID:30873003. That system does not establish an endogenous human Q14114 isoform-specific oligomer state.
ApoER2 ligand-binding domains interact with several alphavirus glycoproteins PMID:34929721. The follow-up cryo-EM structures are explicitly alphavirus spikes bound to the VLDLR ligand-binding domain, not LRP8 structures PMID:39095394. More recently, direct human-cell evidence identified LRP8 as a tick-borne encephalitis virus receptor PMID:40993380. These are well-supported secondary microbial-entry functions, not replacements for endogenous ApoE/Reelin receptor biology.
The four PDB cross-references cover restricted residue spans—3A7Q residues 42-83, 5B4X residues 42-736, 5B4Y residues 42-124, and 7UCX residues 47-65—so none is a full-length LRP8 structure [file:human/LRP8/LRP8-uniprot.txt "DR PDB; 5B4X; X-ray; 3.20 A; B/D=42-736."]. PANTHER PTHR22722:SF15 carries the broad label “LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED” [file:human/LRP8/LRP8-uniprot.txt "DR PANTHER; PTHR22722:SF15; LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED; 1."], consistent with a mixed LDLR/VLDLR/LRP4/LRP8 family grouping rather than an LRP8-specific experimental assignment.
Several seeded sources require conservative handling. PMID:20005821 describes LDLR overexpression in transgenic mouse brain and does not mention LRP8 in the cached abstract PMID:20005821. PMID:23382219 describes promiscuous PX-FERM cargo recognition without explicit LRP8 evidence in the cached main narrative, and PMID:33961781 is a proteome-scale AP-MS network paper rather than an LRP8-specific mechanistic study. Abstract-only access must not be used to overrule experimental curator judgments; such annotations remain unverified or curator-deferred when the specific assay cannot be seen.