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Protein

Low-density lipoprotein receptor-related protein 6

Gene

Lrp6

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

Functioni

Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalsomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity).By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, Receptor
Biological processEndocytosis, Wnt signaling pathway

Names & Taxonomyi

Protein namesi
Recommended name:
Low-density lipoprotein receptor-related protein 6
Short name:
LRP-6
Gene namesi
Name:Lrp6
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1298218 Lrp6

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini20 – 1370ExtracellularSequence analysisAdd BLAST1351
Transmembranei1371 – 1393HelicalSequence analysisAdd BLAST23
Topological domaini1394 – 1613CytoplasmicSequence analysisAdd BLAST220

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Membrane

Pathology & Biotechi

Involvement in diseasei

Defects in Lrp6 are the cause of Ringelschwanz (rs) phenotype. Rs phenotype is a spontaneous mutation that is characterized by a combination of multiple Wnt-deficient phenotypes including dysmorphologies of the axial skeleton, digits and the neural tube. The establishment of the anteroposterior somite compartments, the epithelialization of nascent somites, and the formation of segment borders are disturbed in (rs) mutants. There is delayed ossification at birth and a low bone mass phenotype in adults. Functional analyzes reveal impaired targeting to the plasma surface due to reduced interaction with MESD leading to inhibited Wnt/beta-catenin signaling.2 Publications

Keywords - Diseasei

Disease mutation

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19Sequence analysisAdd BLAST19
ChainiPRO_000001733120 – 1613Low-density lipoprotein receptor-related protein 6Add BLAST1594

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi42N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi81N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi281N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi286 ↔ 297PROSITE-ProRule annotation
Disulfide bondi293 ↔ 308PROSITE-ProRule annotation
Disulfide bondi310 ↔ 323PROSITE-ProRule annotation
Glycosylationi433N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi486N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi592 ↔ 603PROSITE-ProRule annotation
Disulfide bondi599 ↔ 612PROSITE-ProRule annotation
Disulfide bondi614 ↔ 627PROSITE-ProRule annotation
Glycosylationi692N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi859N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi865N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi893 ↔ 904PROSITE-ProRule annotation
Disulfide bondi900 ↔ 914PROSITE-ProRule annotation
Disulfide bondi916 ↔ 929PROSITE-ProRule annotation
Glycosylationi926N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi1207 ↔ 1218PROSITE-ProRule annotation
Disulfide bondi1214 ↔ 1228PROSITE-ProRule annotation
Disulfide bondi1230 ↔ 1243PROSITE-ProRule annotation
Disulfide bondi1249 ↔ 1263PROSITE-ProRule annotation
Disulfide bondi1256 ↔ 1276PROSITE-ProRule annotation
Disulfide bondi1270 ↔ 1285PROSITE-ProRule annotation
Disulfide bondi1288 ↔ 1300PROSITE-ProRule annotation
Disulfide bondi1295 ↔ 1313PROSITE-ProRule annotation
Disulfide bondi1307 ↔ 1322PROSITE-ProRule annotation
Disulfide bondi1326 ↔ 1338PROSITE-ProRule annotation
Disulfide bondi1333 ↔ 1351PROSITE-ProRule annotation
Disulfide bondi1345 ↔ 1360PROSITE-ProRule annotation
Lipidationi1394S-palmitoyl cysteineBy similarity1
Lipidationi1399S-palmitoyl cysteineBy similarity1
Cross-linki1403Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei1420Phosphoserine; by CK1By similarity1
Modified residuei1430Phosphoserine; by CK1By similarity1
Modified residuei1479PhosphothreonineBy similarity1
Modified residuei1490Phosphoserine; by CDK14, GRK5 and GRK6By similarity1
Modified residuei1493Phosphothreonine; by CK1By similarity1

Post-translational modificationi

Dual phosphorylation of cytoplasmic PPPSP motifs sequentially by GSK3 and CK1 is required for AXIN1-binding, and subsequent stabilization and activation of beta-catenin via preventing GSK3-mediated phosphorylation of beta-catenin. Phosphorylated, in vitro, by GRK5/6 within and outside the PPPSP motifs. Phosphorylation at Ser-1490 by CDK14 during G2/M phase leads to regulation of the Wnt signaling pathway during the cell cycle. Phosphorylation by GSK3B is induced by RPSO1 binding and inhibited by DKK1. Phosphorylated, in vitro, by casein kinase I on Thr-1479 (By similarity).By similarity
Undergoes gamma-secretase-dependent regulated intramembrane proteolysis (RIP). The extracellular domain is first released by shedding, and then, through the action of gamma-secretase, the intracellular domain (ICD) is released into the cytoplasm where it is free to bind to GSK3B and to activate canonical Wnt signaling (By similarity).By similarity
Palmitoylation on the two sites near the transmembrane domain leads to release of LRP6 from the endoplasmic reticulum.By similarity
Mono-ubiquitinated which retains LRP6 in the endoplasmic reticulum. Ubiquitinated by ZNRF3, leading to its degradation by the proteasome (By similarity).By similarity
N-glycosylation is required for cell surface location.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Isopeptide bond, Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiO88572
PaxDbiO88572
PeptideAtlasiO88572
PRIDEiO88572

PTM databases

iPTMnetiO88572
PhosphoSitePlusiO88572

Expressioni

Tissue specificityi

Expressed in early embryo. Broadly expressed throughout the embryonic ectoderm and in nascent mesoderm, and in endoderm emerging from the primitive streak.1 Publication

Interactioni

Subunit structurei

Homodimer; disulfide-linked (By similarity). Forms phosphorylated oligomer aggregates on Wnt-signaling (By similarity). Component of the Wnt-Fzd-LRP5-LRP6 complex. Interacts (via the extracellular domain) with WNT1; the interaction is enhanced by prior formation of the Wnt/Fzd complex. Interacts (via the beta-propeller regions 3 and 4) with WNT3A. Interacts (via the beta-propeller regions 1 and 2) with WNT9B. Interacts with FZD5; the interaction forms a coreceptor complex for Wnt signaling and is inhibited by DKK1 and DRAXIN. Interacts (via beta propeller region) with DKK1; the interaction inhibits FZD5/LRP6 complex formation. Interacts with DKK2. Interacts (via the phosphorylated PPPSP motifs) with AXIN1; the interaction recruits the AXIN1/GSK3B complex to cell surface LRP6 signalsomes. Interacts (via the extracellular domain) with RSPO1; the interaction activates Wnt/beta-catenin signaling. Interacts (via the extracellular domain) with RSPO3 (via the cysteine rich domain); the interaction activates Wnt/beta-catenin signaling. Interacts (via the beta-propeller regions 1 and 2) with SOST; the interaction competes with DKK1 for binding for inhibiting beta-catenin signaling. Interacts (via the cytoplasmic domain) with CSNKIE; the interaction phosphorylates LRP6, binds AXIN1 and inhibits AXIN1/GSK3B-mediated phosphorylation of beta-catenin (By similarity). Interacts with DRAXIN; the interaction inhibits Wnt signaling. Interacts with GRB10; the interaction prevents AXIN1 binding, thus negatively regulating the Wnt signaling pathway. Interacts with MESD; the interaction prevents the formation of LRP6 aggregates and targets LRP6 to the plasma membrane. Interacts with MACF1. Interacts with DAB2; the interaction involves LRP6 phosphorylation by CK2 and sequesters LRP6 towards clathrin-mediated endocytosis. Interacts with TMEM198 (By similarity). Interacts with CAPRIN2; the interaction promotes LRP6 phosphorylation at Ser-1490 (By similarity). Found in a complex with CAPRIN2, CCNY and CDK14 during G2/M stage; CAPRIN2 functions as a scaffold for the complex by binding to CCNY via its N terminus and to CDK14 via its C terminus. Interacts with LYPD6. Forms a ternary complex with DKK1 and KREM1 (By similarity). Interacts with KREM1 in a DKK1-dependent manner (By similarity).By similarity5 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi201203, 9 interactors
CORUMiO88572
DIPiDIP-46460N
IntActiO88572, 7 interactors
MINTiO88572
STRINGi10090.ENSMUSP00000032322

Structurei

3D structure databases

ProteinModelPortaliO88572
SMRiO88572
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati63 – 106LDL-receptor class B 1Add BLAST44
Repeati107 – 149LDL-receptor class B 2Add BLAST43
Repeati150 – 193LDL-receptor class B 3Add BLAST44
Repeati194 – 235LDL-receptor class B 4Add BLAST42
Repeati236 – 277LDL-receptor class B 5Add BLAST42
Domaini282 – 324EGF-like 1Add BLAST43
Repeati372 – 414LDL-receptor class B 6Add BLAST43
Repeati415 – 457LDL-receptor class B 7Add BLAST43
Repeati458 – 501LDL-receptor class B 8Add BLAST44
Repeati502 – 542LDL-receptor class B 9Add BLAST41
Repeati543 – 587LDL-receptor class B 10Add BLAST45
Domaini588 – 628EGF-like 2Add BLAST41
Repeati674 – 716LDL-receptor class B 11Add BLAST43
Repeati717 – 759LDL-receptor class B 12Add BLAST43
Repeati760 – 802LDL-receptor class B 13Add BLAST43
Repeati803 – 842LDL-receptor class B 14Add BLAST40
Repeati843 – 885LDL-receptor class B 15Add BLAST43
Domaini889 – 930EGF-like 3Add BLAST42
Repeati977 – 1025LDL-receptor class B 16Add BLAST49
Repeati1026 – 1068LDL-receptor class B 17Add BLAST43
Repeati1069 – 1113LDL-receptor class B 18Add BLAST45
Repeati1114 – 1156LDL-receptor class B 19Add BLAST43
Repeati1157 – 1198LDL-receptor class B 20Add BLAST42
Domaini1203 – 1244EGF-like 4Add BLAST42
Domaini1248 – 1286LDL-receptor class A 1PROSITE-ProRule annotationAdd BLAST39
Domaini1287 – 1323LDL-receptor class A 2PROSITE-ProRule annotationAdd BLAST37
Domaini1325 – 1361LDL-receptor class A 3PROSITE-ProRule annotationAdd BLAST37

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni20 – 275Beta-propeller 1Add BLAST256
Regioni328 – 589Beta-propeller 2Add BLAST262
Regioni631 – 890Beta-propeller 3Add BLAST260
Regioni933 – 1202Beta-propeller 4Add BLAST270

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi1487 – 1493PPPSP motif A7
Motifi1527 – 1534PPPSP motif B8
Motifi1568 – 1575PPPSP motif C8
Motifi1588 – 1593PPPSP motif D6
Motifi1603 – 1610PPPSP motif E8

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi1469 – 1475Poly-Ser7
Compositional biasi1566 – 1573Poly-Pro8
Compositional biasi1603 – 1608Poly-Pro6

Domaini

The YWTD-EGF-like domains 1 and 2 are required for the interaction with Wnt-frizzled complex. The YWTD-EGF-like domains 3 and 4 are required for the interaction with DKK1 (By similarity).By similarity
The PPPSP motifs play a central role in signal transduction by being phosphorylated, leading to activate the Wnt signaling pathway.

Sequence similaritiesi

Belongs to the LDLR family.Curated

Keywords - Domaini

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

Phylogenomic databases

eggNOGiENOG410IPT4 Eukaryota
ENOG410XSY5 LUCA
HOGENOMiHOG000230697
HOVERGENiHBG049167
InParanoidiO88572
KOiK03068
PhylomeDBiO88572
TreeFamiTF315253

Family and domain databases

CDDicd00112 LDLa, 3 hits
Gene3Di2.120.10.30, 4 hits
InterProiView protein in InterPro
IPR011042 6-blade_b-propeller_TolB-like
IPR000742 EGF-like_dom
IPR036055 LDL_receptor-like_sf
IPR023415 LDLR_class-A_CS
IPR000033 LDLR_classB_rpt
IPR002172 LDrepeatLR_classA_rpt
IPR017049 LRP5/6
PfamiView protein in Pfam
PF00057 Ldl_recept_a, 3 hits
PF00058 Ldl_recept_b, 11 hits
PIRSFiPIRSF036314 LDL_recpt-rel_p5/6, 1 hit
PRINTSiPR00261 LDLRECEPTOR
SMARTiView protein in SMART
SM00181 EGF, 4 hits
SM00192 LDLa, 3 hits
SM00135 LY, 20 hits
SUPFAMiSSF57424 SSF57424, 3 hits
PROSITEiView protein in PROSITE
PS01186 EGF_2, 1 hit
PS01209 LDLRA_1, 3 hits
PS50068 LDLRA_2, 3 hits
PS51120 LDLRB, 20 hits

Sequence (1+)i

Sequence statusi: Complete.

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

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.iShow all

O88572-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MGAVLRSLLA CSFCVLLRAA PLLLYANRRD LRLVDATNGK ENATIVVGGL
60 70 80 90 100
EDAAAVDFVF GHGLIYWSDV SEEAIKRTEF NKSESVQNVV VSGLLSPDGL
110 120 130 140 150
ACDWLGEKLY WTDSETNRIE VSNLDGSLRK VLFWQELDQP RAIALDPSSG
160 170 180 190 200
FMYWTDWGEV PKIERAGMDG SSRFVIINTE IYWPNGLTLD YQERKLYWAD
210 220 230 240 250
AKLNFIHKSN LDGTNRQAVV KGSLPHPFAL TLFEDTLYWT DWNTHSILAC
260 270 280 290 300
NKYTGEGLRE IHSNIFSPMD IHAFSQQRQP NATNPCGIDN GGCSHLCLMS
310 320 330 340 350
PVKPFYQCAC PTGVKLMENG KTCKDGATEL LLLARRTDLR RISLDTPDFT
360 370 380 390 400
DIVLQLEDIR HAIAIDYDPV EGYIYWTDDE VRAIRRSFID GSGSQFVVTA
410 420 430 440 450
QIAHPDGIAV DWVARNLYWT DTGTDRIEVT RLNGTMRKIL ISEDLEEPRA
460 470 480 490 500
IVLDPMVGYM YWTDWGEIPK IERAALDGSD RVVLVNTSLG WPNGLALDYD
510 520 530 540 550
EGTIYWGDAK TDKIEVMNTD GTGRRVLVED KIPHIFGFTL LGDYVYWTDW
560 570 580 590 600
QRRSIERVHK RSAEREVIID QLPDLMGLKA TSVHRVIGSN PCAEDNGGCS
610 620 630 640 650
HLCLYRPQGL RCACPIGFEL IGDMKTCIVP EAFLLFSRRA DIRRISLETN
660 670 680 690 700
NNNVAIPLTG VKEASALDFD VTDNRIYWTD ISLKTISRAF MNGSALEHVV
710 720 730 740 750
EFGLDYPEGM AVDWLGKNLY WADTGTNRIE VSKLDGQHRQ VLVWKDLDSP
760 770 780 790 800
RALALDPAEG FMYWTEWGGK PKIDRAAMDG SERTTLVPNV GRANGLTIDY
810 820 830 840 850
AKRRLYWTDL DTNLIESSDM LGLNREVIAD DLPHPFGLTQ YQDYIYWTDW
860 870 880 890 900
SRRSIERANK TSGQNRTIIQ GHLDYVMDIL VFHSSRQAGW NECASSNGHC
910 920 930 940 950
SHLCLAVPVG GFVCGCPAHY SLNADNRTCS APSTFLLFSQ KSAINRMVID
960 970 980 990 1000
EQQSPDIILP IHSLRNVRAI DYDPLDKQLY WIDSRQNSIR KAHEDGGQGF
1010 1020 1030 1040 1050
NVVANSVANQ NLEIQPYDLS IDIYSRYIYW TCEATNVIDV TRLDGRSVGV
1060 1070 1080 1090 1100
VLKGEQDRPR AIVVNPEKGY MYFTNLQERS PKIERAALDG TEREVLFFSG
1110 1120 1130 1140 1150
LSKPIALALD SKLGKLFWAD SDLRRIESSD LSGANRIVLE DSNILQPVGL
1160 1170 1180 1190 1200
TVFENWLYWI DKQQQMIEKI DMTGREGRTK VQARIAQLSD IHAVKELNLQ
1210 1220 1230 1240 1250
EYRQHPCAQD NGGCSHICLV KGDGTTRCSC PMHLVLLQDE LSCGEPPTCS
1260 1270 1280 1290 1300
PQQFTCFTGD IDCIPVAWRC DGFTECEDHS DELNCPVCSE SQFQCASGQC
1310 1320 1330 1340 1350
IDGALRCNGD ANCQDKSDEK NCEVLCLIDQ FRCANGQCVG KHKKCDHSVD
1360 1370 1380 1390 1400
CSDRSDELDC YPTEEPAPQA TNTVGSVIGV IVTIFVSGTI YFICQRMLCP
1410 1420 1430 1440 1450
RMKGDGETMT NDYVVHSPAS VPLGYVPHPS SLSGSLPGMS RGKSMISSLS
1460 1470 1480 1490 1500
IMGGSSGPPY DRAHVTGASS SSSSSTKGTY FPAILNPPPS PATERSHYTM
1510 1520 1530 1540 1550
EFGYSSNSPS THRSYSYRPY SYRHFAPPTT PCSTDVCDSD YAPSRRMTSV
1560 1570 1580 1590 1600
ATAKGYTSDV NYDSEPVPPP PTPRSQYLSA EENYESCPPS PYTERSYSHH
1610
LYPPPPSPCT DSS
Length:1,613
Mass (Da):180,255
Last modified:November 1, 1998 - v1
Checksum:i3C2ABC8EEEB17622
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A0R4J0A9A0A0R4J0A9_MOUSE
Low-density lipoprotein receptor-re...
Lrp6
1,613Annotation score:
A0A0N4SUL9A0A0N4SUL9_MOUSE
Low-density lipoprotein receptor-re...
Lrp6
131Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti83S → T in AAH60704 (PubMed:15489334).Curated1
Sequence conflicti317M → L in AAH60704 (PubMed:15489334).Curated1
Sequence conflicti586V → I in AAH60704 (PubMed:15489334).Curated1
Sequence conflicti622G → S in AAH60704 (PubMed:15489334).Curated1
Sequence conflicti933S → T in AAH60704 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti886R → W in rs. 2 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF074265 mRNA Translation: AAC33007.1
BC060704 mRNA Translation: AAH60704.1
CCDSiCCDS39678.1
PIRiJE0273
RefSeqiNP_032540.2, NM_008514.4
UniGeneiMm.321990

Genome annotation databases

GeneIDi16974
KEGGimmu:16974
UCSCiuc009ekl.2 mouse

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiLRP6_MOUSE
AccessioniPrimary (citable) accession number: O88572
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 10, 2004
Last sequence update: November 1, 1998
Last modified: September 12, 2018
This is version 156 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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