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Protein

Low-density lipoprotein receptor-related protein 8

Gene

Lrp8

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.1 Publication

GO - Molecular functioni

  • apolipoprotein binding Source: BHF-UCL
  • calcium-dependent protein binding Source: BHF-UCL
  • calcium ion binding Source: InterPro
  • glycoprotein binding Source: BHF-UCL
  • low-density lipoprotein receptor activity Source: MGI
  • reelin receptor activity Source: BHF-UCL
  • very-low-density lipoprotein particle receptor activity Source: MGI

GO - Biological processi

  • ammon gyrus development Source: BHF-UCL
  • chemical synaptic transmission Source: CACAO
  • dendrite morphogenesis Source: CACAO
  • endocytosis Source: UniProtKB
  • hippocampus development Source: MGI
  • layer formation in cerebral cortex Source: MGI
  • modulation of synaptic transmission Source: BHF-UCL
  • negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • positive regulation of CREB transcription factor activity Source: BHF-UCL
  • positive regulation of dendrite development Source: BHF-UCL
  • positive regulation of dendritic spine morphogenesis Source: BHF-UCL
  • positive regulation of peptidyl-tyrosine phosphorylation Source: BHF-UCL
  • positive regulation of protein kinase activity Source: MGI
  • positive regulation of protein tyrosine kinase activity Source: BHF-UCL
  • reelin-mediated signaling pathway Source: BHF-UCL
  • ventral spinal cord development Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Receptor

Keywords - Biological processi

Endocytosis

Keywords - Ligandi

Calcium

Enzyme and pathway databases

ReactomeiR-MMU-432142. Platelet sensitization by LDL.
R-MMU-975634. Retinoid metabolism and transport.

Protein family/group databases

TCDBi9.B.87.1.9. the selenoprotein p receptor (selp-receptor) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Low-density lipoprotein receptor-related protein 8
Short name:
LRP-8
Alternative name(s):
Apolipoprotein E receptor 2
Gene namesi
Name:Lrp8
Synonyms:Apoer2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1340044. Lrp8.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini29 – 858ExtracellularSequence analysisAdd BLAST830
Transmembranei859 – 881HelicalSequence analysisAdd BLAST23
Topological domaini882 – 996CytoplasmicSequence analysisAdd BLAST115

GO - Cellular componenti

  • caveola Source: MGI
  • extracellular space Source: BHF-UCL
  • integral component of membrane Source: UniProtKB-KW
  • membrane Source: MGI
  • plasma membrane Source: MGI
  • receptor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi61D → N: Lower affinity for RAP. Abolishes binding to Reelin. 1 Publication1
Mutagenesisi102E → Q: Same affinity for RAP. Same affinity for Reelin. 1 Publication1
Mutagenesisi145E → Q: Same affinity for RAP. Lower affinity for Reelin. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 28Sequence analysisAdd BLAST28
ChainiPRO_000001733329 – 996Low-density lipoprotein receptor-related protein 8Add BLAST968

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi41 ↔ 53By similarity
Disulfide bondi48 ↔ 66By similarity
Disulfide bondi60 ↔ 75By similarity
Disulfide bondi80 ↔ 92By similarity
Disulfide bondi87 ↔ 105By similarity
Disulfide bondi99 ↔ 116By similarity
Disulfide bondi121 ↔ 135By similarity
Disulfide bondi128 ↔ 148By similarity
Disulfide bondi142 ↔ 157By similarity
Disulfide bondi161 ↔ 173By similarity
Disulfide bondi168 ↔ 186By similarity
Glycosylationi170N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi180 ↔ 195By similarity
Disulfide bondi200 ↔ 213By similarity
Disulfide bondi207 ↔ 226By similarity
Disulfide bondi220 ↔ 237By similarity
Disulfide bondi251 ↔ 264By similarity
Disulfide bondi259 ↔ 277By similarity
Disulfide bondi271 ↔ 286By similarity
Disulfide bondi291 ↔ 303By similarity
Disulfide bondi298 ↔ 316By similarity
Disulfide bondi310 ↔ 325By similarity
Disulfide bondi331 ↔ 344By similarity
Disulfide bondi339 ↔ 357By similarity
Disulfide bondi351 ↔ 368By similarity
Disulfide bondi373 ↔ 384By similarity
Disulfide bondi380 ↔ 393By similarity
Disulfide bondi395 ↔ 407By similarity
Disulfide bondi413 ↔ 423By similarity
Disulfide bondi419 ↔ 432By similarity
Disulfide bondi434 ↔ 447By similarity
Glycosylationi551N-linked (GlcNAc...)Sequence analysis1
Glycosylationi805N-linked (GlcNAc...)Sequence analysis1
Glycosylationi840N-linked (GlcNAc...)Sequence analysis1

Post-translational modificationi

O-glycosylated. Some alternatively spliced isoforms lack the O-linked sugar domain.1 Publication
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.2 Publications
Tyrosine phosphorylated upon apoE binding.By similarity
Ubiquitinated by MYLIP leading to degradation.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiQ924X6.

PTM databases

iPTMnetiQ924X6.
PhosphoSitePlusiQ924X6.

Expressioni

Tissue specificityi

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.1 Publication

Developmental stagei

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

Gene expression databases

BgeeiENSMUSG00000028613.
ExpressionAtlasiQ924X6. baseline and differential.
GenevisibleiQ924X6. MM.

Interactioni

Subunit structurei

Reelin associates with two or more receptor molecules. Interacts with DAB1 and JNK-interacting proteins. Interacts with SNX17. Interacts with PCSK9 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Dlg4Q621083EBI-432319,EBI-300895
Grin1P354384EBI-432319,EBI-400084
Lrpap1Q990682EBI-432319,EBI-919734From a different organism.
RelnQ608414EBI-432319,EBI-9248666

GO - Molecular functioni

  • apolipoprotein binding Source: BHF-UCL
  • calcium-dependent protein binding Source: BHF-UCL

Protein-protein interaction databases

DIPiDIP-33284N.
IntActiQ924X6. 7 interactors.
MINTiMINT-111626.

Structurei

3D structure databases

ProteinModelPortaliQ924X6.
SMRiQ924X6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini40 – 76LDL-receptor class A 1PROSITE-ProRule annotationAdd BLAST37
Domaini79 – 117LDL-receptor class A 2PROSITE-ProRule annotationAdd BLAST39
Domaini120 – 158LDL-receptor class A 3PROSITE-ProRule annotationAdd BLAST39
Domaini160 – 196LDL-receptor class A 4PROSITE-ProRule annotationAdd BLAST37
Domaini199 – 238LDL-receptor class A 5PROSITE-ProRule annotationAdd BLAST40
Domaini250 – 287LDL-receptor class A 6PROSITE-ProRule annotationAdd BLAST38
Domaini290 – 326LDL-receptor class A 7PROSITE-ProRule annotationAdd BLAST37
Domaini330 – 369LDL-receptor class A 8PROSITE-ProRule annotationAdd BLAST40
Domaini364 – 408EGF-like 1PROSITE-ProRule annotationAdd BLAST45
Domaini409 – 448EGF-like 2; calcium-bindingPROSITE-ProRule annotationAdd BLAST40
Repeati495 – 541LDL-receptor class B 1Add BLAST47
Repeati542 – 584LDL-receptor class B 2Add BLAST43
Repeati585 – 628LDL-receptor class B 3Add BLAST44
Repeati629 – 671LDL-receptor class B 4Add BLAST43
Repeati672 – 714LDL-receptor class B 5Add BLAST43

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni773 – 831Clustered O-linked oligosaccharidesAdd BLAST59

Domaini

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 similaritiesi

Belongs to the LDLR family.Curated
Contains 2 EGF-like domains.PROSITE-ProRule annotation
Contains 8 LDL-receptor class A domains.PROSITE-ProRule annotation
Contains 5 LDL-receptor class B repeats.PROSITE-ProRule annotation

Keywords - Domaini

EGF-like domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

GeneTreeiENSGT00760000118968.
HOGENOMiHOG000115656.
HOVERGENiHBG006250.
InParanoidiQ924X6.
OMAiWRCDEDN.
PhylomeDBiQ924X6.

Family and domain databases

Gene3Di2.120.10.30. 1 hit.
4.10.400.10. 8 hits.
InterProiIPR011042. 6-blade_b-propeller_TolB-like.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000742. EGF-like_dom.
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]
PfamiPF07645. EGF_CA. 1 hit.
PF00057. Ldl_recept_a. 8 hits.
PF00058. Ldl_recept_b. 5 hits.
[Graphical view]
PRINTSiPR00261. LDLRECEPTOR.
SMARTiSM00181. EGF. 4 hits.
SM00179. EGF_CA. 2 hits.
SM00192. LDLa. 8 hits.
SM00135. LY. 5 hits.
[Graphical view]
SUPFAMiSSF57424. SSF57424. 8 hits.
PROSITEiPS00010. 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]

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q924X6-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MGRPELGALR PLALLLLLLL QLQHLSAADP LPGGQGPVKE CEEDQFRCRN
60 70 80 90 100
ERCIPLVWRC DEDNDCSDNS DEDDCPKRTC ADSDFTCDNG HCIPERWKCD
110 120 130 140 150
GEEECPDGSD ESKATCSSEE CPAEKLSCGP TSHKCVPASW RCDGEKDCEG
160 170 180 190 200
GADEAGCPTL CAPHEFQCSN RSCLASVFVC DGDDDCGDGS DERGCSDPAC
210 220 230 240 250
PPREFRCGGG GTCIPERWVC DRQFDCEDRS DEAAELCGRA GQGTTATPAA
260 270 280 290 300
CAPTAQFTCR SGECIHLGWR CDGDRDCKDK SDEADCSPGP CRENEFQCGD
310 320 330 340 350
GTCVLAIKRC NQERDCPDGS DEAGCLQEST CEGPRRFQCK SGECVDGGKV
360 370 380 390 400
CDDQRDCRDW SDEPQKVCGL NECLHNNGGC SHICTDLKIG FECTCPAGFQ
410 420 430 440 450
LLDQKTCGDI DECQDPDACS QICVNYKGYF KCECHPGYEM DTLTKNCKAV
460 470 480 490 500
AGKSPSLIFT NRHEVRRIDL VKRDYSRLIP MLKNVVALDV EVATNRIYWC
510 520 530 540 550
DLSYRKIYSA HMDKASIPDE QVVLIDEQLH SPEGLAVDWV HKHIYWTDSG
560 570 580 590 600
NKTISVATTD GRRRCTLFSR ELSEPRAIAV DPLRGFMYWS DWGFQAKIEK
610 620 630 640 650
AGLNGADRQT LVSDNIEWPN GITLDLLSQR LYWVDSKLHQ LSSIDFNGGN
660 670 680 690 700
RKMLIFSTDF LSHPFGVAVF EDKVFWTDLE NEAIFSANRL NGLEIAILAE
710 720 730 740 750
NLNNPHDIVI FHELKQPKAA DACDLSAQPN GGCEYLCLPA PQISSHSPKY
760 770 780 790 800
TCACPDTMWL GPDMKRCYRA PQSTSTTTLA SAMTRTVPAT TRAPGTTIHD
810 820 830 840 850
PTYQNHSTET PSQTAAAPHS VNVPRAPSTS PSTPSPATSN HSQHYGNEGS
860 870 880 890 900
QMGSTVTAAV IGVIVPIVVI ALLCMSGYLI WRNWKRKNTK SMNFDNPVYR
910 920 930 940 950
KTTEEEEEDE LHIGRTAQIG HVYPAAISNY DRPLWAEPCL GETRDLEDPA
960 970 980 990
PALKELFVLP GEPRSQLHQL PKNPLSELPV VKCKRVALSL EDDGLP
Length:996
Mass (Da):109,818
Last modified:May 10, 2004 - v2
Checksum:iBA1AF0132A964EBA
GO
Isoform 2 (identifier: Q924X6-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     160-285: Missing.

Note: No experimental confirmation available.
Show »
Length:870
Mass (Da):96,351
Checksum:i3531262B7C9D6446
GO
Isoform 3 (identifier: Q924X6-5)
Also known as: ApoER2delta4-6,8-F
Sequence is not available
Note: Contains a 18 aa insert in the extracellular part which carries a furin cleavage site.
Length:
Mass (Da):

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti32P → L in BAB46965 (PubMed:9685741).Curated1
Sequence conflicti286 – 287CS → SA (PubMed:11294845).Curated2
Sequence conflicti610T → P in CAC38356 (PubMed:11294845).Curated1
Sequence conflicti672 – 673DK → VQ in CAC38356 (PubMed:11294845).Curated2
Sequence conflicti715 – 716KQ → NE in CAC38356 (PubMed:11294845).Curated2
Sequence conflicti750Y → F in CAC38356 (PubMed:11294845).Curated1
Sequence conflicti766R → K in CAC38356 (PubMed:11294845).Curated1
Sequence conflicti802T → A in CAC38356 (PubMed:11294845).Curated1
Sequence conflicti815 – 817AAA → VAV in CAC38356 (PubMed:11294845).Curated3

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_010309160 – 285Missing in isoform 2. 1 PublicationAdd BLAST126

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D85463 mRNA. Translation: BAB46965.1.
AJ312058 mRNA. Translation: CAC38356.1.
CCDSiCCDS51255.1. [Q924X6-2]
PIRiJE0237.
RefSeqiXP_011238759.1. XM_011240457.2. [Q924X6-1]
UniGeneiMm.442134.

Genome annotation databases

EnsembliENSMUST00000143601; ENSMUSP00000115854; ENSMUSG00000028613. [Q924X6-1]
GeneIDi16975.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D85463 mRNA. Translation: BAB46965.1.
AJ312058 mRNA. Translation: CAC38356.1.
CCDSiCCDS51255.1. [Q924X6-2]
PIRiJE0237.
RefSeqiXP_011238759.1. XM_011240457.2. [Q924X6-1]
UniGeneiMm.442134.

3D structure databases

ProteinModelPortaliQ924X6.
SMRiQ924X6.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-33284N.
IntActiQ924X6. 7 interactors.
MINTiMINT-111626.

Protein family/group databases

TCDBi9.B.87.1.9. the selenoprotein p receptor (selp-receptor) family.

PTM databases

iPTMnetiQ924X6.
PhosphoSitePlusiQ924X6.

Proteomic databases

PRIDEiQ924X6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000143601; ENSMUSP00000115854; ENSMUSG00000028613. [Q924X6-1]
GeneIDi16975.

Organism-specific databases

CTDi7804.
MGIiMGI:1340044. Lrp8.

Phylogenomic databases

GeneTreeiENSGT00760000118968.
HOGENOMiHOG000115656.
HOVERGENiHBG006250.
InParanoidiQ924X6.
OMAiWRCDEDN.
PhylomeDBiQ924X6.

Enzyme and pathway databases

ReactomeiR-MMU-432142. Platelet sensitization by LDL.
R-MMU-975634. Retinoid metabolism and transport.

Miscellaneous databases

PROiQ924X6.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000028613.
ExpressionAtlasiQ924X6. baseline and differential.
GenevisibleiQ924X6. MM.

Family and domain databases

Gene3Di2.120.10.30. 1 hit.
4.10.400.10. 8 hits.
InterProiIPR011042. 6-blade_b-propeller_TolB-like.
IPR001881. EGF-like_Ca-bd_dom.
IPR013032. EGF-like_CS.
IPR000742. EGF-like_dom.
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]
PfamiPF07645. EGF_CA. 1 hit.
PF00057. Ldl_recept_a. 8 hits.
PF00058. Ldl_recept_b. 5 hits.
[Graphical view]
PRINTSiPR00261. LDLRECEPTOR.
SMARTiSM00181. EGF. 4 hits.
SM00179. EGF_CA. 2 hits.
SM00192. LDLa. 8 hits.
SM00135. LY. 5 hits.
[Graphical view]
SUPFAMiSSF57424. SSF57424. 8 hits.
PROSITEiPS00010. 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]
ProtoNetiSearch...

Entry informationi

Entry nameiLRP8_MOUSE
AccessioniPrimary (citable) accession number: Q924X6
Secondary accession number(s): Q8CAK9, Q8CDF5, Q921B6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 10, 2004
Last sequence update: May 10, 2004
Last modified: November 2, 2016
This is version 146 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.