This reference pass reviewed the four seeded GO_REF records, both seeded PubMed
records, five decisive cached primary papers, and the current reviewed UniProt
record. Direct human APP-sorting and endogenous brain-cell localization studies
receive the greatest weight. Mouse beta-VLDL uptake supports a narrow ortholog
inference; HuRI interactions remain screen observations; and disease-associated
variants or stressed overexpression models are not treated as definitions of
normal core function.
Human LRP10 is UniProtKB Q7Z4F1, a reviewed 713-residue precursor
[file:human/LRP10/LRP10-uniprot.txt, "ID LRP10_HUMAN Reviewed; 713 AA."].
The record places the signal peptide at residues 1-16, the extracellular region
at 17-440, the transmembrane helix at 441-461, and the cytoplasmic tail at
462-713 [file:human/LRP10/LRP10-uniprot.txt, "FT TRANSMEM 441..461"].
Domain resources record two CUB domains and four LDLRA repeats
[file:human/LRP10/LRP10-uniprot.txt, "DR SMART; SM00042; CUB; 2.";
"DR SMART; SM00192; LDLa; 4."].
The exact PANTHER assignment is PTHR24270:SF17
[file:human/LRP10/LRP10-uniprot.txt, "DR PANTHER; PTHR24270:SF17; LOW-DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 10; 1."].
The reviewed member boundary used here is narrow—human Q7Z4F1 and mouse Q7TQH7—
whereas parent PTHR24270 is a broad LDL-receptor-related family. Parent-family
properties therefore should not be transferred as though every LDLR paralog had
LRP10 substrate specificity.
UniProt isoform 2 lacks residues 557-713
[file:human/LRP10/LRP10-uniprot.txt, "FT /note=\"Missing (in isoform 2)\""].
This deletes much of the long cytoplasmic tail, but no reviewed source here
demonstrates an isoform-2-specific localization or function. Disease-associated
splice products must not be conflated with this normal alternative product.
The record has an AlphaFoldDB cross-reference
[file:human/LRP10/LRP10-uniprot.txt, "DR AlphaFoldDB; Q7Z4F1; -."], but no
experimental PDB cross-reference. Structural claims are consequently domain-
and prediction-level, not experimentally solved full-length structures.
The strongest direct human functional study identifies APP as an LRP10 cargo.
Biochemical mapping concluded that "LRP10 interacts directly and predominantly with the ectodomain of APP in vitro." PMID:22734645. In cultured cells, surface
LRP10 is internalized into early endosomes and returned to the Golgi: "After rapid internalization in early endosomes, LRP10 is recycled back to the Golgi, a step that requires the DXXLL motifs in the cytoplasmic tail of LRP10 ."
PMID:22734645. These results support a type-I cargo/sorting receptor whose
cytoplasmic tail controls itinerary; they do not imply an enzyme activity.
In human SH-SY5Y neuroblastoma cells, increased LRP10 retained mature APP in the
Golgi and reduced its surface abundance and Aβ processing, while depletion
increased Aβ production [PMID:22734645, "knockdown of LRP10 expression
increases Aβ production."]. These are direct cultured-cell findings, but the
paper's Alzheimer-disease interpretation should not be generalized into a
universal in-vivo disease mechanism.
PMID:11123907 characterized the mouse ortholog under the historical name LRP9;
the abstract explicitly says it arose from "a mouse lymphocyte cDNA library."
The functional assay found that "Apolipoprotein E (apoE)-enriched beta-VLDL stimulated cellular
cholesteryl ester formation in ldl-A7/LRP9."
PMID:11123907. This supports ortholog transfer of very-low-density-lipoprotein
particle receptor activity, not direct human Q7Z4F1 activity and not blanket
LDL-particle receptor activity.
The strongest localization study used post-mortem human brain and control
iPSC-derived cells with knockout-validated antibodies. It reports that LRP10 is
mainly expressed in astrocytes and neurovasculature and was undetectable in the
examined neurons; iPSC-derived astrocytes likewise expressed LRP10 whereas the
examined iPSC-derived neurons did not [PMID:33913039, "LRP10 is highly
expressed in iPSC-derived astrocytes but cannot be observed in iPSC-derived
neurons."]. In astrocytes, LRP10 was found at the TGN, plasma membrane,
retromer, and early endosomes and "partially
co-localises and interacts with sortilin-related receptor 1 (SORL1)." PMID:33913039. This directly supports a
non-neuronal vesicle-trafficking context and SORL1 association, without proving
a constitutive binary complex in every cell type.
The HuRI paper constructed a proteome-scale binary interaction map using nine
screens and "pairwise verification by quadruplicate retesting and sequence confirmation" PMID:32296183. The 21 LRP10 partners in GOA/IntAct are valid
screen observations, but their diversity and lack of targeted physiological
validation prevent a shared mechanistic function or native complex from being
assigned. Generic protein binding is therefore non-core.
PMID:19946888 is a membrane-proteome survey of the human NK-like YTS cell line
[PMID:19946888, "The present study was initiated to define the composition of the membrane"]. Its cached abstract does not name LRP10 or expose the protein/
peptide table. The seeded HDA membrane assignment is retained with curator
deference, but the source cannot independently establish a more specific
compartment from the accessible record.
The 2018 genetics paper found rare variants across familial Parkinson disease,
Parkinson disease dementia, and dementia with Lewy bodies. It explicitly calls
the segregation support "independent-albeit limited-evidence" and reports
variant-specific effects on mRNA, protein stability, or localization
PMID:29887161. These results motivate loss-of-function hypotheses but do not
establish a core disease process or show that every LRP10 variant has the same
mechanism.
The 2024 study reports that wild-type LRP10 is secreted in extracellular
vesicles and can be internalized by clathrin-dependent endocytosis in its cell
and organoid systems [PMID:38315424, "Here, we demonstrate that
wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be
internalised via clathrin-dependent endocytosis."]. It also links LRP10 overexpression and a
patient-derived splice product to changes in α-synuclein. The authors explicitly
identify "our model to study LRP10 and α-synuclein has important limitations, including overexpression, the use of non-neural cell lines, and the lack of the aging component of LBDs" PMID:38315424. These
are valuable disease-context mechanisms, not evidence that constitutive EV
secretion or α-synuclein regulation is the normal universal core function of
LRP10.