Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q924X6 (LRP8_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 127. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Low-density lipoprotein receptor-related protein 8

Short name=LRP-8
Alternative name(s):
Apolipoprotein E receptor 2
Gene names
Name:Lrp8
Synonyms:Apoer2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length996 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands. LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail. Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons. LRP8 has higher affinity for Reelin than VLDLR. LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development. Binds the endoplasmic reticulum resident receptor-associated protein (RAP). 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. May also function as an endocytic receptor. Ref.6

Subunit structure

Reelin associates with two or more receptor molecules. Interacts with DAB1 and JNK-interacting proteins. Interacts with SNX17. Interacts with PCSK9 By similarity. Ref.2 Ref.3 Ref.7 Ref.8 Ref.9

Subcellular location

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

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. Ref.8

Developmental stage

Expressed from embryonic day E12 to E16. Mice which are deficient in LRP8 have neuronal migration defect.

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.

Post-translational modification

O-glycosylated. Some alternatively spliced isoforms lack the O-linked sugar domain. Ref.4

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 By similarity.

Ubiquitinated by MYLIP leading to degradation By similarity.

Miscellaneous

LRP8 and VLVLR together are required for correct embryonic development in the brain. Targeted disruption of both genes results in a phenotype virtually indistinguishable from that seen in "reeler" and "scrambler" mice. 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. Besides brain formation defects, LRP8-deficient mice also exhibit male infertility.

Sequence similarities

Belongs to the LDLR family.

Contains 2 EGF-like domains.

Contains 8 LDL-receptor class A domains.

Contains 5 LDL-receptor class B repeats.

Ontologies

Keywords
   Biological processEndocytosis
   Cellular componentCell membrane
Membrane
Secreted
   Coding sequence diversityAlternative splicing
   DomainEGF-like domain
Repeat
Signal
Transmembrane
Transmembrane helix
   LigandCalcium
   Molecular functionReceptor
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processammon gyrus development

Inferred from mutant phenotype PubMed 18778775. Source: BHF-UCL

endocytosis

Inferred from sequence or structural similarity. Source: UniProtKB

hippocampus development

Inferred from genetic interaction PubMed 17330141. Source: MGI

layer formation in cerebral cortex

Inferred from genetic interaction PubMed 17330141. Source: MGI

negative regulation of transcription from RNA polymerase II promoter

Inferred from mutant phenotype PubMed 18778775. Source: BHF-UCL

positive regulation of CREB transcription factor activity

Inferred from mutant phenotype PubMed 21852430. Source: BHF-UCL

positive regulation of dendrite development

Inferred from genetic interaction PubMed 18778775. Source: BHF-UCL

positive regulation of dendritic spine morphogenesis

Inferred from mutant phenotype PubMed 21852430. Source: BHF-UCL

positive regulation of peptidyl-tyrosine phosphorylation

Inferred from mutant phenotype PubMed 21852430. Source: BHF-UCL

positive regulation of protein kinase activity

Inferred from genetic interaction PubMed 12526740. Source: MGI

positive regulation of protein tyrosine kinase activity

Inferred from mutant phenotype PubMed 21852430. Source: BHF-UCL

receptor-mediated endocytosis

Traceable author statement Ref.2Ref.1. Source: GOC

reelin-mediated signaling pathway

Inferred from mutant phenotype PubMed 18778775PubMed 21852430. Source: BHF-UCL

regulation of synaptic transmission

Inferred from mutant phenotype PubMed 18778775. Source: BHF-UCL

ventral spinal cord development

Inferred from expression pattern PubMed 20711475. Source: UniProtKB

   Cellular_componentextracellular space

Inferred from direct assay PubMed 15950758. Source: BHF-UCL

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

plasma membrane

Traceable author statement Ref.2. Source: MGI

receptor complex

Inferred from sequence orthology PubMed 23382219. Source: MGI

   Molecular_functionapolipoprotein binding

Inferred from direct assay PubMed 10571240. Source: BHF-UCL

calcium ion binding

Inferred from electronic annotation. Source: InterPro

calcium-dependent protein binding

Inferred from physical interaction PubMed 10571240. Source: BHF-UCL

glycoprotein binding

Inferred from physical interaction PubMed 10571240. Source: BHF-UCL

low-density lipoprotein receptor activity

Traceable author statement Ref.2Ref.1. Source: MGI

protein binding

Inferred from physical interaction PubMed 16332682. Source: IntAct

reelin receptor activity

Inferred from mutant phenotype PubMed 18778775. Source: BHF-UCL

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Dlg4Q621083EBI-432319,EBI-300895
Grin1P354384EBI-432319,EBI-400084

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: 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.
Isoform 2 (identifier: Q924X6-2)

The sequence of this isoform differs from the canonical sequence as follows:
     160-285: Missing.
Note: No experimental confirmation available.
Isoform 3 (identifier: Q924X6-5)

Also known as: ApoER2delta4-6,8-F;

The sequence of this isoform is not available.
Note: Contains a 18 aa insert in the extracellular part which carries a furin cleavage site.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2828 Potential
Chain29 – 996968Low-density lipoprotein receptor-related protein 8
PRO_0000017333

Regions

Topological domain29 – 858830Extracellular Potential
Transmembrane859 – 88123Helical; Potential
Topological domain882 – 996115Cytoplasmic Potential
Domain40 – 7637LDL-receptor class A 1
Domain79 – 11739LDL-receptor class A 2
Domain120 – 15839LDL-receptor class A 3
Domain160 – 19637LDL-receptor class A 4
Domain199 – 23840LDL-receptor class A 5
Domain250 – 28738LDL-receptor class A 6
Domain290 – 32637LDL-receptor class A 7
Domain330 – 36940LDL-receptor class A 8
Domain364 – 40845EGF-like 1
Domain409 – 44840EGF-like 2; calcium-binding Potential
Repeat495 – 54147LDL-receptor class B 1
Repeat542 – 58443LDL-receptor class B 2
Repeat585 – 62844LDL-receptor class B 3
Repeat629 – 67143LDL-receptor class B 4
Repeat672 – 71443LDL-receptor class B 5
Region773 – 83159Clustered O-linked oligosaccharides

Amino acid modifications

Glycosylation1701N-linked (GlcNAc...) Potential
Glycosylation5511N-linked (GlcNAc...) Potential
Glycosylation8051N-linked (GlcNAc...) Potential
Glycosylation8401N-linked (GlcNAc...) Potential
Disulfide bond41 ↔ 53 By similarity
Disulfide bond48 ↔ 66 By similarity
Disulfide bond60 ↔ 75 By similarity
Disulfide bond80 ↔ 92 By similarity
Disulfide bond87 ↔ 105 By similarity
Disulfide bond99 ↔ 116 By similarity
Disulfide bond121 ↔ 135 By similarity
Disulfide bond128 ↔ 148 By similarity
Disulfide bond142 ↔ 157 By similarity
Disulfide bond161 ↔ 173 By similarity
Disulfide bond168 ↔ 186 By similarity
Disulfide bond180 ↔ 195 By similarity
Disulfide bond200 ↔ 213 By similarity
Disulfide bond207 ↔ 226 By similarity
Disulfide bond220 ↔ 237 By similarity
Disulfide bond251 ↔ 264 By similarity
Disulfide bond259 ↔ 277 By similarity
Disulfide bond271 ↔ 286 By similarity
Disulfide bond291 ↔ 303 By similarity
Disulfide bond298 ↔ 316 By similarity
Disulfide bond310 ↔ 325 By similarity
Disulfide bond331 ↔ 344 By similarity
Disulfide bond339 ↔ 357 By similarity
Disulfide bond351 ↔ 368 By similarity
Disulfide bond373 ↔ 384 By similarity
Disulfide bond380 ↔ 393 By similarity
Disulfide bond395 ↔ 407 By similarity
Disulfide bond413 ↔ 423 By similarity
Disulfide bond419 ↔ 432 By similarity
Disulfide bond434 ↔ 447 By similarity

Natural variations

Alternative sequence160 – 285126Missing in isoform 2.
VSP_010309

Experimental info

Mutagenesis611D → N: Lower affinity for RAP. Abolishes binding to Reelin.
Mutagenesis1021E → Q: Same affinity for RAP. Same affinity for Reelin.
Mutagenesis1451E → Q: Same affinity for RAP. Lower affinity for Reelin.
Sequence conflict321P → L in BAB46965. Ref.1
Sequence conflict286 – 2872CS → SA Ref.2
Sequence conflict6101T → P in CAC38356. Ref.2
Sequence conflict672 – 6732DK → VQ in CAC38356. Ref.2
Sequence conflict715 – 7162KQ → NE in CAC38356. Ref.2
Sequence conflict7501Y → F in CAC38356. Ref.2
Sequence conflict7661R → K in CAC38356. Ref.2
Sequence conflict8021T → A in CAC38356. Ref.2
Sequence conflict815 – 8173AAA → VAV in CAC38356. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified May 10, 2004. Version 2.
Checksum: BA1AF0132A964EBA

FASTA996109,818
        10         20         30         40         50         60 
MGRPELGALR PLALLLLLLL QLQHLSAADP LPGGQGPVKE CEEDQFRCRN ERCIPLVWRC 

        70         80         90        100        110        120 
DEDNDCSDNS DEDDCPKRTC ADSDFTCDNG HCIPERWKCD GEEECPDGSD ESKATCSSEE 

       130        140        150        160        170        180 
CPAEKLSCGP TSHKCVPASW RCDGEKDCEG GADEAGCPTL CAPHEFQCSN RSCLASVFVC 

       190        200        210        220        230        240 
DGDDDCGDGS DERGCSDPAC PPREFRCGGG GTCIPERWVC DRQFDCEDRS DEAAELCGRA 

       250        260        270        280        290        300 
GQGTTATPAA CAPTAQFTCR SGECIHLGWR CDGDRDCKDK SDEADCSPGP CRENEFQCGD 

       310        320        330        340        350        360 
GTCVLAIKRC NQERDCPDGS DEAGCLQEST CEGPRRFQCK SGECVDGGKV CDDQRDCRDW 

       370        380        390        400        410        420 
SDEPQKVCGL NECLHNNGGC SHICTDLKIG FECTCPAGFQ LLDQKTCGDI DECQDPDACS 

       430        440        450        460        470        480 
QICVNYKGYF KCECHPGYEM DTLTKNCKAV AGKSPSLIFT NRHEVRRIDL VKRDYSRLIP 

       490        500        510        520        530        540 
MLKNVVALDV EVATNRIYWC DLSYRKIYSA HMDKASIPDE QVVLIDEQLH SPEGLAVDWV 

       550        560        570        580        590        600 
HKHIYWTDSG NKTISVATTD GRRRCTLFSR ELSEPRAIAV DPLRGFMYWS DWGFQAKIEK 

       610        620        630        640        650        660 
AGLNGADRQT LVSDNIEWPN GITLDLLSQR LYWVDSKLHQ LSSIDFNGGN RKMLIFSTDF 

       670        680        690        700        710        720 
LSHPFGVAVF EDKVFWTDLE NEAIFSANRL NGLEIAILAE NLNNPHDIVI FHELKQPKAA 

       730        740        750        760        770        780 
DACDLSAQPN GGCEYLCLPA PQISSHSPKY TCACPDTMWL GPDMKRCYRA PQSTSTTTLA 

       790        800        810        820        830        840 
SAMTRTVPAT TRAPGTTIHD PTYQNHSTET PSQTAAAPHS VNVPRAPSTS PSTPSPATSN 

       850        860        870        880        890        900 
HSQHYGNEGS QMGSTVTAAV IGVIVPIVVI ALLCMSGYLI WRNWKRKNTK SMNFDNPVYR 

       910        920        930        940        950        960 
KTTEEEEEDE LHIGRTAQIG HVYPAAISNY DRPLWAEPCL GETRDLEDPA PALKELFVLP 

       970        980        990 
GEPRSQLHQL PKNPLSELPV VKCKRVALSL EDDGLP 

« Hide

Isoform 2 [UniParc].

Checksum: 3531262B7C9D6446
Show »

FASTA87096,351
Isoform 3 (ApoER2delta4-6,8-F) (Sequence not available).

References

[1]"Evolution of the apolipoprotein E receptor 2 gene by exon loss."
Kim H.-J., Kim D.-H., Magoori K., Saeki S., Yamamoto T.
J. Biochem. 124:451-456(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Brain.
[2]"Alternative splicing in the ligand binding domain of mouse ApoE receptor-2 produces receptor variants binding reelin but not alpha2-macroglobulin."
Brandes C., Kahr L., Stockinger W., Hiesberger T., Schneider W.J., Nimpf J.
J. Biol. Chem. 276:22160-22169(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING, INTERACTION WITH REELIN AND ALPHA2-MACROGLOBULIN.
[3]"The PX-domain protein SNX17 interacts with members of the LDL receptor family and modulates endocytosis of the LDL receptor."
Stockinger W., Sailler B., Strasser V., Recheis B., Fasching D., Kahr L., Schneider W.J., Nimpf J.
EMBO J. 21:4259-4267(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SNX17.
[4]"Differential glycosylation regulates processing of lipoprotein receptors by gamma-secretase."
May P., Bock H.H., Nimpf J., Herz J.
J. Biol. Chem. 278:37386-37392(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING, GLYCOSYLATION, PROTEOLYTIC PROCESSING.
[5]"A secreted soluble form of ApoE receptor 2 acts as a dominant-negative receptor and inhibits Reelin signaling."
Koch S., Strasser V., Hauser C., Fasching D., Brandes C., Bajari T.M., Schneider W.J., Nimpf J.
EMBO J. 21:5996-6004(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING, PROTEOLYTIC PROCESSING.
[6]"Essential role of the apolipoprotein E receptor-2 in sperm development."
Andersen O.M., Yeung C.H., Vorum H., Wellner M., Andreassen T.K., Erdmann B., Mueller E.C., Herz J., Otto A., Cooper T.G., Willnow T.E.
J. Biol. Chem. 278:23989-23995(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SPERM DEVELOPMENT.
[7]"Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2."
Trommsdorff M., Gotthardt M., Hiesberger T., Shelton J., Stockinger W., Nimpf J., Hammer R.E., Richardson J.A., Herz J.
Cell 97:689-701(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAB1.
[8]"The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2."
Stockinger W., Brandes C., Fasching D., Hermann M., Gotthardt M., Herz J., Schneider W.J., Nimpf J.
J. Biol. Chem. 275:25625-25632(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH JNK-INTERACTING PROTEINS, TISSUE SPECIFICITY.
[9]"Differential binding of ligands to the apolipoprotein E receptor 2."
Andersen O.M., Benhayon D., Curran T., Willnow T.E.
Biochemistry 42:9355-9364(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RAP AND REELIN, STOICHIOMETRY, MUTAGENESIS.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D85463 mRNA. Translation: BAB46965.1.
AJ312058 mRNA. Translation: CAC38356.1.
CCDSCCDS51255.1. [Q924X6-2]
PIRJE0237.
UniGeneMm.442134.

3D structure databases

ProteinModelPortalQ924X6.
SMRQ924X6. Positions 39-767.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-33284N.
IntActQ924X6. 5 interactions.
MINTMINT-111626.

Protein family/group databases

TCDB9.B.87.2.1. the selenoprotein p receptor (selp-receptor) family.

PTM databases

PhosphoSiteQ924X6.

Proteomic databases

PaxDbQ924X6.
PRIDEQ924X6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000143601; ENSMUSP00000115854; ENSMUSG00000028613. [Q924X6-1]

Organism-specific databases

MGIMGI:1340044. Lrp8.

Phylogenomic databases

eggNOGNOG255913.
GeneTreeENSGT00740000114992.
HOGENOMHOG000115656.
HOVERGENHBG006250.
InParanoidQ924X6.
OMAGCLQEST.
OrthoDBEOG7NGQ9P.
PhylomeDBQ924X6.

Gene expression databases

ArrayExpressQ924X6.
BgeeQ924X6.
GenevestigatorQ924X6.

Family and domain databases

Gene3D2.120.10.30. 1 hit.
4.10.400.10. 8 hits.
InterProIPR011042. 6-blade_b-propeller_TolB-like.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR018097. EGF_Ca-bd_CS.
IPR023415. LDLR_class-A_CS.
IPR000033. LDLR_classB_rpt.
IPR002172. LDrepeatLR_classA_rpt.
[Graphical view]
PfamPF07645. EGF_CA. 1 hit.
PF00057. Ldl_recept_a. 8 hits.
PF00058. Ldl_recept_b. 5 hits.
[Graphical view]
PRINTSPR00261. LDLRECEPTOR.
SMARTSM00181. EGF. 2 hits.
SM00179. EGF_CA. 1 hit.
SM00192. LDLa. 8 hits.
SM00135. LY. 5 hits.
[Graphical view]
SUPFAMSSF57424. SSF57424. 8 hits.
PROSITEPS00010. ASX_HYDROXYL. 2 hits.
PS01186. EGF_2. 2 hits.
PS50026. EGF_3. 2 hits.
PS01187. EGF_CA. 1 hit.
PS01209. LDLRA_1. 8 hits.
PS50068. LDLRA_2. 8 hits.
PS51120. LDLRB. 5 hits.
[Graphical view]
ProtoNetSearch...

Other

NextBio13887235.
PROQ924X6.
SOURCESearch...

Entry information

Entry nameLRP8_MOUSE
AccessionPrimary (citable) accession number: Q924X6
Secondary accession number(s): Q8CAK9, Q8CDF5, Q921B6
Entry history
Integrated into UniProtKB/Swiss-Prot: May 10, 2004
Last sequence update: May 10, 2004
Last modified: July 9, 2014
This is version 127 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot