LDLR review notes

Deep research: the client reported a timeout after 600 s on 2026-10-09, so the review was done
manually from the GOA-cited publications cached in publications/ and the UniProt record. The
provider in fact finished (run ended 2026-10-09T16:41) and LDLR-deep-research-falcon.md was
written afterwards. It was checked against this review on 2026-10-11:

• It agrees on the core annotation: surface recognition and clathrin-mediated endocytosis of
  apoB-100- and apoE-bearing lipoprotein particles, acid-dependent cargo release in the
  endosome via the LA-repeat/beta-propeller closed conformation, and receptor recycling. It
  stresses that the substrate is the apolipoprotein-bearing particle rather than free
  cholesterol, and that LDLR is not an enzyme or a sterol transporter. This matches core
  functions 1 and 2 and the review's rejection of generic transporter terms.
• It confirms the regulatory layer the review annotates: SREBP-2/SCAP transcriptional control,
  PCSK9 binding to EGF-A diverting the receptor to lysosomes (including an intracellular
  trans-Golgi route), and LXR-induced IDOL/MYLIP ubiquitination of the cytosolic tail.
• It adds the Reimund et al. cryo-EM structure of apoB-100-containing LDL bound to LDLR
  (Nature 638, online 2024-12-11; ~5.6 and ~7.9 A), which resolves two interfaces: the LA
  modules contact basic regions of the apoB-100 beta-belt, and the beta-propeller contacts the
  apoB-100 N-terminal domain. This is direct structural support for core function 1; the
  resolution does not support residue-level claims.
• It flags a specificity caveat the review should not overstate: the 2024 Commander/Retriever
  recycling work (Butkovic et al.) used LRP1 and other cargoes, not LDLR, so endosomal
  recycling machinery beyond the FDNPVY/ARH/AP-2 step is not LDLR-specific evidence. The
  review annotates only the adaptor step (GO:0035612), which is unaffected.
• It does not discuss the VSV entry-receptor role (PMID:23589850), reviewed here separately.

Core biology (with provenance)

• LDLR binds LDL and carries it into cells by endocytosis; complexes must cluster in clathrin-coated
  pits [file:human/LDLR/LDLR-uniprot.txt "Binds low density lipoprotein /LDL, the major
  cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis."]
• Functional surface receptors after cDNA transfection PMID:6091915
• FH alleles dissect synthesis, transport and binding PMID:6299582
• Internalization signal FDNPVY is read by AP-2 mu2 (so the clathrin-heavy-chain-binding annotation
  was modified to AP-2 adaptor complex binding) PMID:12121421
• apoE-containing ligands (beta-VLDL) also bind PMID:2777800
• Endosomal closed conformation and recycling PMID:26526611
• Degradation by PCSK9 PMID:17452316 and by IDOL PMID:19520913

Curation decisions worth flagging

• PCSK9-driven regulation terms (negative regulation of receptor recycling, negative regulation of
  LDL particle clearance) annotated to LDLR describe the regulator's role; marked over-annotated on
  LDLR (they are accepted on PCSK9).
• GO:0030299 intestinal cholesterol absorption (IMP, PMID:17142622): the cached full text of this UK
  FH genetics study contains no intestinal data; marked over-annotated rather than removed.
• Brain amyloid-beta / apoE clearance terms from mouse overexpression (PMID:20005821) kept as non-core;
  downstream neuroinflammation terms marked over-annotated.

Disease alignment

dismech LDLR-Related_Familial_Hypercholesterolemia binds the trigger node to GO:0005041 (DECREASED),
matching core function 1 here. Its class-3 node was corrected (2026-10-09) from GO:0050750 (the
ligand-side receptor-binding term) to GO:0030169 low-density lipoprotein particle binding, the
receptor's own binding function.