Q924X6 · LRP8_MOUSE

  • Protein
    Low-density lipoprotein receptor-related protein 8
  • Gene
    Lrp8
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands (PubMed:10380922, PubMed:11294845, PubMed:12899622, PubMed:18778775).
LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail (PubMed:10380922).
Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons (PubMed:10380922).
LRP8 has higher affinity for Reelin than VLDLR (PubMed:10380922, PubMed:11294845).
LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development (PubMed:10380922, PubMed:11294845, PubMed:18778775).
Binds the endoplasmic reticulum resident receptor-associated protein (RAP) (PubMed:12899622).
Binds dimers of beta 2-glycoprotein I and may be involved in the suppression of platelet aggregation in the vasculature. Highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation (PubMed:12695510).
May also function as an endocytic receptor (PubMed:12169628).
Not required for endocytic uptake of SEPP1 in the kidney which is mediated by LRP2 (PubMed:18174160).
Together with its ligand, apolipoprotein E (apoE), may indirectly play a role in the suppression of the innate immune response by controlling the survival of myeloid-derived suppressor cells (PubMed:29336888).

Features

Showing features for binding site.

TypeIDPosition(s)Description
Binding site58Ca2+ (UniProtKB | ChEBI)
Binding site61Ca2+ (UniProtKB | ChEBI)
Binding site63Ca2+ (UniProtKB | ChEBI)
Binding site65Ca2+ (UniProtKB | ChEBI)
Binding site71Ca2+ (UniProtKB | ChEBI)
Binding site72Ca2+ (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentaxon
Cellular Componentcaveola
Cellular Componentcell surface
Cellular Componentdendrite
Cellular Componentextracellular space
Cellular Componentglutamatergic synapse
Cellular Componentmicrotubule associated complex
Cellular Componentneuronal cell body
Cellular Componentplasma membrane
Cellular Componentpostsynaptic density membrane
Cellular Componentreceptor complex
Cellular ComponentSchaffer collateral - CA1 synapse
Molecular Functionamyloid-beta binding
Molecular Functionapolipoprotein binding
Molecular Functioncalcium ion binding
Molecular Functioncalcium-dependent protein binding
Molecular Functionhigh-density lipoprotein particle binding
Molecular Functionkinesin binding
Molecular Functionlow-density lipoprotein particle receptor activity
Molecular Functionreelin receptor activity
Molecular Functionvery-low-density lipoprotein particle receptor activity
Biological Processammon gyrus development
Biological Processcellular response to cholesterol
Biological Processcellular response to growth factor stimulus
Biological Processchemical synaptic transmission
Biological Processdendrite morphogenesis
Biological Processendocytosis
Biological Processhippocampus development
Biological Processlayer formation in cerebral cortex
Biological Processmodulation of chemical synaptic transmission
Biological Processpositive regulation of dendrite development
Biological Processpositive regulation of dendritic spine morphogenesis
Biological Processreelin-mediated signaling pathway
Biological Processregulation of apoptotic process
Biological Processregulation of innate immune response
Biological Processresponse to xenobiotic stimulus
Biological Processventral spinal cord development

Keywords

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomy

Protein names

  • Recommended name
    Low-density lipoprotein receptor-related protein 8
  • Short names
    LRP-8
  • Alternative names
    • Apolipoprotein E receptor 2

Gene names

    • Name
      Lrp8
    • Synonyms
      Apoer2

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    Q924X6
  • Secondary accessions
    • Q8CAK9
    • Q8CDF5
    • Q921B6

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane
; Single-pass type I membrane protein
Secreted
Note: Isoforms that contain the exon coding for a furin-type cleavage site are proteolytically processed, leading to a secreted receptor fragment.

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain29-858Extracellular
Transmembrane859-881Helical
Topological domain882-996Cytoplasmic

Keywords

Phenotypes & Variants

Disruption phenotype

Mice which are deficient in LRP8 have neuronal migration defect (PubMed:10380922, PubMed:18778775).
Targeted disruption of LRP8 and VLVLR together results in a phenotype virtually indistinguishable from that seen in 'reeler' and 'scrambler' mice (PubMed:10380922).
Subtle effects of VLDLR deletion are found mainly in the cerebellum, whereas lack of LRP8 predominantly affects the positioning of the neurons in the neocortex (PubMed:10380922).
Besides brain formation defects, LRP8-deficient mice also exhibit male infertility (PubMed:10380922).
Does not affect endocytosis of SEPP1 in the kidney proximal tubule (PubMed:18174160).

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis61Lower affinity for RAP. Abolishes binding to Reelin.
Mutagenesis102Same affinity for RAP. Same affinity for Reelin.
Mutagenesis145Same affinity for RAP. Lower affinity for Reelin.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 41 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

PTM/Processing

Features

Showing features for signal, chain, disulfide bond, glycosylation.

TypeIDPosition(s)Description
Signal1-28
ChainPRO_000001733329-996
Disulfide bond41↔53
Disulfide bond48↔66
Disulfide bond60↔75
Disulfide bond80↔92
Disulfide bond87↔105
Disulfide bond99↔116
Disulfide bond121↔135
Disulfide bond128↔148
Disulfide bond142↔157
Disulfide bond161↔173
Disulfide bond168↔186
Glycosylation170N-linked (GlcNAc...) asparagine
Disulfide bond180↔195
Disulfide bond200↔213
Disulfide bond207↔226
Disulfide bond220↔237
Disulfide bond251↔264
Disulfide bond259↔277
Disulfide bond271↔286
Disulfide bond291↔303
Disulfide bond298↔316
Disulfide bond310↔325
Disulfide bond331↔344
Disulfide bond339↔357
Disulfide bond351↔368
Disulfide bond373↔384
Disulfide bond380↔393
Disulfide bond395↔407
Disulfide bond413↔423
Disulfide bond419↔432
Disulfide bond434↔447
Glycosylation551N-linked (GlcNAc...) asparagine
Glycosylation805N-linked (GlcNAc...) asparagine
Glycosylation840N-linked (GlcNAc...) asparagine

Post-translational modification

O-glycosylated. Some alternatively spliced isoforms lack the O-linked sugar domain.
Undergoes sequential, furin and gamma-secretase dependent, proteolytic processing, resulting in the extracellular release of the entire ligand-binding domain as a soluble polypeptide and in the intracellular domain (ICD) release into the cytoplasm. The gamma-secretase-dependent proteolytical processing occurs after the bulk of the extracellular domain has been shed, in a furin-dependent manner, in alternatively spliced isoforms carrying the furin cleavage site. Hypoglycosylation (mainly hypo-O-glycosylation) leads to increased extracellular cleavage, which in turn results in accelerating release of the intracellular domain (ICD) by the gamma-secretase. The resulting receptor fragment is able to inhibit Reelin signaling and in particular the Reelin-induced DAB1 phosphorylation.
Tyrosine phosphorylated upon apoE binding.
Ubiquitinated by MYLIP leading to degradation.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Expressed in neurons throughout the brain, with strong expression in pyramidal neurons of the hippocampus, granule cells of the dentate gyrus, cortical neurons and Purkinje cells of the cerebellum. Also expressed in the epithelium of the choroid plexus and of the blood vessels (apical expression), as well as in the epididymis.

Gene expression databases

Interaction

Subunit

Homooligomer (By similarity).
Interacts with VLDLR (By similarity).
Reelin associates with two or more receptor molecules. Interacts with DAB1 and JNK-interacting proteins. Interacts with SNX17. Interacts with PCSK9 (By similarity).
Interacts with MDK; this interaction is calcium dependent (PubMed:12573468).
Interacts with CLU (By similarity).

Binary interactions

Protein-protein interaction databases

Miscellaneous

Structure

Family & Domains

Features

Showing features for domain, repeat, region.

TypeIDPosition(s)Description
Domain40-76LDL-receptor class A 1
Domain79-117LDL-receptor class A 2
Domain120-158LDL-receptor class A 3
Domain160-196LDL-receptor class A 4
Domain199-238LDL-receptor class A 5
Domain250-287LDL-receptor class A 6
Domain290-326LDL-receptor class A 7
Domain330-369LDL-receptor class A 8
Domain364-408EGF-like 1
Domain409-448EGF-like 2; calcium-binding
Repeat495-541LDL-receptor class B 1
Repeat542-584LDL-receptor class B 2
Repeat585-628LDL-receptor class B 3
Repeat629-671LDL-receptor class B 4
Repeat672-714LDL-receptor class B 5
Region773-831Clustered O-linked oligosaccharides
Region778-851Disordered

Domain

The cytoplasmic domain is involved in the binding of DAB1 and in the recruitment of JNK-interacting proteins. Isoforms, which lack part of the cytoplasmic domain, are unable to recruit members of the family of JNK interacting proteins (JIP) to the cytoplasmic tail.

Sequence similarities

Belongs to the LDLR family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence & Isoforms

Align isoforms (3)
  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.

This entry describes 3 isoforms produced by Alternative splicing.

Q924X6-1

This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

  • Length
    996
  • Mass (Da)
    109,818
  • Last updated
    2004-05-10 v2
  • Checksum
    BA1AF0132A964EBA
MGRPELGALRPLALLLLLLLQLQHLSAADPLPGGQGPVKECEEDQFRCRNERCIPLVWRCDEDNDCSDNSDEDDCPKRTCADSDFTCDNGHCIPERWKCDGEEECPDGSDESKATCSSEECPAEKLSCGPTSHKCVPASWRCDGEKDCEGGADEAGCPTLCAPHEFQCSNRSCLASVFVCDGDDDCGDGSDERGCSDPACPPREFRCGGGGTCIPERWVCDRQFDCEDRSDEAAELCGRAGQGTTATPAACAPTAQFTCRSGECIHLGWRCDGDRDCKDKSDEADCSPGPCRENEFQCGDGTCVLAIKRCNQERDCPDGSDEAGCLQESTCEGPRRFQCKSGECVDGGKVCDDQRDCRDWSDEPQKVCGLNECLHNNGGCSHICTDLKIGFECTCPAGFQLLDQKTCGDIDECQDPDACSQICVNYKGYFKCECHPGYEMDTLTKNCKAVAGKSPSLIFTNRHEVRRIDLVKRDYSRLIPMLKNVVALDVEVATNRIYWCDLSYRKIYSAHMDKASIPDEQVVLIDEQLHSPEGLAVDWVHKHIYWTDSGNKTISVATTDGRRRCTLFSRELSEPRAIAVDPLRGFMYWSDWGFQAKIEKAGLNGADRQTLVSDNIEWPNGITLDLLSQRLYWVDSKLHQLSSIDFNGGNRKMLIFSTDFLSHPFGVAVFEDKVFWTDLENEAIFSANRLNGLEIAILAENLNNPHDIVIFHELKQPKAADACDLSAQPNGGCEYLCLPAPQISSHSPKYTCACPDTMWLGPDMKRCYRAPQSTSTTTLASAMTRTVPATTRAPGTTIHDPTYQNHSTETPSQTAAAPHSVNVPRAPSTSPSTPSPATSNHSQHYGNEGSQMGSTVTAAVIGVIVPIVVIALLCMSGYLIWRNWKRKNTKSMNFDNPVYRKTTEEEEEDELHIGRTAQIGHVYPAAISNYDRPLWAEPCLGETRDLEDPAPALKELFVLPGEPRSQLHQLPKNPLSELPVVKCKRVALSLEDDGLP

Q924X6-2

  • Name
    2
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Differences from canonical

Q924X6-5

  • Name
    3
  • Synonyms
    ApoER2delta4-6,8-F
  • Note
    Contains a 18 aa insert in the extracellular part which carries a furin cleavage site.
  • See also
    sequence in UniParc or sequence clusters in UniRef

Computationally mapped potential isoform sequences

There are 12 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
B1AXJ3B1AXJ3_MOUSELrp8832
B1AXJ4B1AXJ4_MOUSELrp8955
B1AXJ5B1AXJ5_MOUSELrp8896
B1AXJ6B1AXJ6_MOUSELrp8694
F6YZZ8F6YZZ8_MOUSELrp8870
A0A571BEC8A0A571BEC8_MOUSELrp8726
A0A571BE80A0A571BE80_MOUSELrp8787
A0A571BE60A0A571BE60_MOUSELrp8828
A0A571BDQ2A0A571BDQ2_MOUSELrp8135
A0A571BDC7A0A571BDC7_MOUSELrp8189
A0A571BGD2A0A571BGD2_MOUSELrp8157
A0A571BEF2A0A571BEF2_MOUSELrp8124

Features

Showing features for sequence conflict, alternative sequence.

TypeIDPosition(s)Description
Sequence conflict32in Ref. 1; BAB46965
Alternative sequenceVSP_010309160-285in isoform 2
Sequence conflict286-287in Ref. 2
Sequence conflict610in Ref. 2; CAC38356
Sequence conflict672-673in Ref. 2; CAC38356
Sequence conflict715-716in Ref. 2; CAC38356
Sequence conflict750in Ref. 2; CAC38356
Sequence conflict766in Ref. 2; CAC38356
Sequence conflict802in Ref. 2; CAC38356
Sequence conflict815-817in Ref. 2; CAC38356

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
D85463
EMBL· GenBank· DDBJ
BAB46965.1
EMBL· GenBank· DDBJ
mRNA
AJ312058
EMBL· GenBank· DDBJ
CAC38356.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

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