Low-density lipoprotein receptor-related protein 8 precursor

Preferred order of sections

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	996 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 process	Endocytosis
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing
Domain	EGF-like domain Repeat Signal Transmembrane Transmembrane helix
Ligand	Calcium
Molecular function	Receptor
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ammon gyrus development Inferred from mutant phenotype PubMed 18778775. Source: BHF-UCL 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 protein tyrosine kinase activity Inferred from mutant phenotype PubMed 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_component	extracellular space Inferred from direct assay PubMed 15950758. Source: BHF-UCL integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Traceable author statement Ref.2. Source: MGI
Molecular_function	apolipoprotein binding Inferred from direct assay PubMed 10571240. Source: BHF-UCL calcium ion binding Inferred from electronic annotation. Source: InterPro low-density lipoprotein receptor activity Traceable author statement Ref.2 Ref.1. Source: MGI reelin receptor activity Inferred from mutant phenotype PubMed 18778775. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Dlg4	Q62108	3	EBI-432319,EBI-300895
Grin1	P35438	4	EBI-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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 28

28

Potential

Chain

29 – 996

968

Low-density lipoprotein receptor-related protein 8

PRO_0000017333

Regions

Topological domain

29 – 858

830

Extracellular Potential

Transmembrane

859 – 881

23

Helical; Potential

Topological domain

882 – 996

115

Cytoplasmic Potential

Domain

40 – 76

37

LDL-receptor class A 1

Domain

79 – 117

39

LDL-receptor class A 2

Domain

120 – 158

39

LDL-receptor class A 3

Domain

160 – 196

37

LDL-receptor class A 4

Domain

199 – 238

40

LDL-receptor class A 5

Domain

250 – 287

38

LDL-receptor class A 6

Domain

290 – 326

37

LDL-receptor class A 7

Domain

330 – 369

40

LDL-receptor class A 8

Domain

364 – 408

45

EGF-like 1

Domain

409 – 448

40

EGF-like 2; calcium-binding Potential

Repeat

495 – 541

47

LDL-receptor class B 1

Repeat

542 – 584

43

LDL-receptor class B 2

Repeat

585 – 628

44

LDL-receptor class B 3

Repeat

629 – 671

43

LDL-receptor class B 4

Repeat

672 – 714

43

LDL-receptor class B 5

Region

773 – 831

59

Clustered O-linked oligosaccharides

Amino acid modifications

Glycosylation

170

1

N-linked (GlcNAc...) Potential

Glycosylation

551

1

N-linked (GlcNAc...) Potential

Glycosylation

805

1

N-linked (GlcNAc...) Potential

Glycosylation

840

1

N-linked (GlcNAc...) Potential

Disulfide bond

41 ↔ 53

By similarity

Disulfide bond

48 ↔ 66

By similarity

Disulfide bond

60 ↔ 75

By similarity

Disulfide bond

80 ↔ 92

By similarity

Disulfide bond

87 ↔ 105

By similarity

Disulfide bond

99 ↔ 116

By similarity

Disulfide bond

121 ↔ 135

By similarity

Disulfide bond

128 ↔ 148

By similarity

Disulfide bond

142 ↔ 157

By similarity

Disulfide bond

161 ↔ 173

By similarity

Disulfide bond

168 ↔ 186

By similarity

Disulfide bond

180 ↔ 195

By similarity

Disulfide bond

200 ↔ 213

By similarity

Disulfide bond

207 ↔ 226

By similarity

Disulfide bond

220 ↔ 237

By similarity

Disulfide bond

251 ↔ 264

By similarity

Disulfide bond

259 ↔ 277

By similarity

Disulfide bond

271 ↔ 286

By similarity

Disulfide bond

291 ↔ 303

By similarity

Disulfide bond

298 ↔ 316

By similarity

Disulfide bond

310 ↔ 325

By similarity

Disulfide bond

331 ↔ 344

By similarity

Disulfide bond

339 ↔ 357

By similarity

Disulfide bond

351 ↔ 368

By similarity

Disulfide bond

373 ↔ 384

By similarity

Disulfide bond

380 ↔ 393

By similarity

Disulfide bond

395 ↔ 407

By similarity

Disulfide bond

413 ↔ 423

By similarity

Disulfide bond

419 ↔ 432

By similarity

Disulfide bond

434 ↔ 447

By similarity

Natural variations

Alternative sequence

160 – 285

126

Missing in isoform 2.

VSP_010309

Experimental info

Mutagenesis

61

1

D → N: Lower affinity for RAP. Abolishes binding to Reelin.

Mutagenesis

102

1

E → Q: Same affinity for RAP. Same affinity for Reelin.

Mutagenesis

145

1

E → Q: Same affinity for RAP. Lower affinity for Reelin.

Sequence conflict

32

1

P → L in BAB46965. Ref.1

Sequence conflict

286 – 287

2

CS → SA Ref.2

Sequence conflict

610

1

T → P in CAC38356. Ref.2

Sequence conflict

672 – 673

2

DK → VQ in CAC38356. Ref.2

Sequence conflict

715 – 716

2

KQ → NE in CAC38356. Ref.2

Sequence conflict

750

1

Y → F in CAC38356. Ref.2

Sequence conflict

766

1

R → K in CAC38356. Ref.2

Sequence conflict

802

1

T → A in CAC38356. Ref.2

Sequence conflict

815 – 817

3

AAA → VAV in CAC38356. Ref.2

Sequences

Sequence

Length

Mass (Da)

Tools

Isoform 1 [UniParc].

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

FASTA

996

109,818

        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 »

FASTA

870

96,351

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.
IPI	IPI00121600. IPI00410868.
PIR	JE0237.
UniGene	Mm.442134.
3D structure databases
ProteinModelPortal	Q924X6.
SMR	Q924X6. Positions 39-767.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-33284N.
IntAct	Q924X6. 5 interactions.
Protein family/group databases
TCDB	9.B.87.2.1. selenoprotein P receptor (SelP-receptor) family.
PTM databases
PhosphoSite	Q924X6.
Proteomic databases
PaxDb	Q924X6.
PRIDE	Q924X6.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000143601; ENSMUSP00000115854; ENSMUSG00000028613.
Organism-specific databases
MGI	MGI:1340044. Lrp8.
Phylogenomic databases
eggNOG	NOG255913.
GeneTree	ENSGT00700000104037.
HOGENOM	HOG000115656.
HOVERGEN	HBG006250.
InParanoid	Q924X6.
OMA	EFQCSNR.
OrthoDB	EOG479F6G.
Gene expression databases
ArrayExpress	Q924X6.
Bgee	Q924X6.
Genevestigator	Q924X6.
Family and domain databases
Gene3D	2.120.10.30. 1 hit. 4.10.400.10. 8 hits.
InterPro	IPR011042. 6-blade_b-propeller_TolB-like. IPR000742. EG-like_dom. IPR001881. EGF-like_Ca-bd. IPR013032. EGF-like_CS. IPR000152. EGF-type_Asp/Asn_hydroxyl_site. IPR018097. EGF_Ca-bd_CS. IPR009030. Growth_fac_rcpt. IPR023415. LDLR_class-A_CS. IPR000033. LDLR_classB_rpt. IPR002172. LDrepeatLR_classA_rpt. [Graphical view]
Pfam	PF07645. EGF_CA. 1 hit. PF00057. Ldl_recept_a. 8 hits. PF00058. Ldl_recept_b. 5 hits. [Graphical view]
SMART	SM00181. EGF. 2 hits. SM00179. EGF_CA. 1 hit. SM00192. LDLa. 8 hits. SM00135. LY. 5 hits. [Graphical view]
SUPFAM	SSF57184. Grow_fac_recept. 1 hit. SSF57424. LDL_rcpt_classA_cys-rich. 6 hits.
PROSITE	PS00010. ASX_HYDROXYL. 2 hits. PS00022. EGF_1. False negative. 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]
ProtoNet	Search...
Other
NextBio	13887235.
SOURCE	Search...

Entry information

Entry name

LRP8_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 115 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

MGD cross-references

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

SIMILARITY comments

Index of protein domains and families

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

Protein family/group databases

PTM databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents