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Protein

Low-density lipoprotein receptor-related protein 6

Gene

LRP6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 similarity10 Publications

GO - Molecular functioni

  • apolipoprotein binding Source: GO_Central
  • coreceptor activity involved in canonical Wnt signaling pathway Source: ParkinsonsUK-UCL
  • coreceptor activity involved in Wnt signaling pathway Source: BHF-UCL
  • frizzled binding Source: BHF-UCL
  • kinase inhibitor activity Source: BHF-UCL
  • low-density lipoprotein receptor activity Source: MGI
  • protein homodimerization activity Source: BHF-UCL
  • receptor binding Source: BHF-UCL
  • toxin transporter activity Source: BHF-UCL
  • Wnt-activated receptor activity Source: GO_Central
  • Wnt-protein binding Source: BHF-UCL

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Receptor

Keywords - Biological processi

Endocytosis, Wnt signaling pathway

Enzyme and pathway databases

BioCyciZFISH:ENSG00000070018-MONOMER.
ReactomeiR-HSA-201681. TCF dependent signaling in response to WNT.
R-HSA-3772470. Negative regulation of TCF-dependent signaling by WNT ligand antagonists.
R-HSA-4641262. Disassembly of the destruction complex and recruitment of AXIN to the membrane.
R-HSA-4641263. Regulation of FZD by ubiquitination.
R-HSA-5340588. RNF mutants show enhanced WNT signaling and proliferation.
SignaLinkiO75581.
SIGNORiO75581.

Names & Taxonomyi

Protein namesi
Recommended name:
Low-density lipoprotein receptor-related protein 6
Short name:
LRP-6
Gene namesi
Name:LRP6
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:6698. LRP6.

Subcellular locationi

Topology

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

GO - Cellular componenti

  • cell surface Source: BHF-UCL
  • cytoplasmic vesicle Source: UniProtKB
  • early endosome membrane Source: Reactome
  • endoplasmic reticulum Source: UniProtKB-SubCell
  • extracellular region Source: Reactome
  • integral component of membrane Source: UniProtKB-KW
  • neuronal cell body Source: GO_Central
  • plasma membrane Source: BHF-UCL
  • receptor complex Source: GO_Central
  • synapse Source: GO_Central
  • Wnt-Frizzled-LRP5/6 complex Source: ParkinsonsUK-UCL
  • Wnt signalosome Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Membrane

Pathology & Biotechi

Involvement in diseasei

Coronary artery disease, autosomal dominant, 2 (ADCAD2)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA common heart disease characterized by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. Its most important complication is acute myocardial infarction.
See also OMIM:610947
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_076208360R → H in ADCAD2. 1 PublicationCorresponds to variant rs141212743dbSNPEnsembl.1
Natural variantiVAR_076209433N → S in ADCAD2. 1 PublicationCorresponds to variant rs397515473dbSNPEnsembl.1
Natural variantiVAR_076210473R → Q in ADCAD2; impairs Wnt signaling. 1 PublicationCorresponds to variant rs397515474dbSNPEnsembl.1
Natural variantiVAR_034701611R → C in ADCAD2; impairs Wnt signaling in vitro. 1 PublicationCorresponds to variant rs121918313dbSNPEnsembl.1
Tooth agenesis, selective, 7 (STHAG7)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth).
See also OMIM:616724
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07620719A → V in STHAG7; impairs Wnt signaling; prevents transport to plasma membrane location. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi1394C → A: Some reduction of palmitoylation, little change in plasma membrane location in the presence of MESD nor in Wnt-signaling activity. Completely abolishes palmitoylation, no plasma membrane location, greatly reduced Wnt-signaling activity but no effect on ubiquitination; when associated with A-1399. Exhibits full Wnt-signaling activity and no change in plasma membrane location; when associated with A-1399 and R-1403. 1 Publication1
Mutagenesisi1399C → A: Some reduction of palmitoylation, and little change in plasma membrane location in the presence of MESD nor in Wnt-signaling activity. Completely abolishes palmitoylation, no plasma membrane location, greatly reduced Wnt-signaling activity but no effect on ubiquitination; when associated with A-1394. Exhibits full Wnt-signaling activity and no change in plasma membrane location in the in presence of MESD; when associated with A-1394 and R-1403. 1 Publication1
Mutagenesisi1403K → R: Abolishes ubiquitination, no change in plasma membrane location in the presence of MESD but greatly reduced Wnt-signaling activity. Exhibits full Wnt-signaling activity and no change in plasma membrane location; when associated with A-1394 and A-1399. 1
Mutagenesisi1420S → A: Enhanced AXIN1 binding and increased beta-catenin activity by 2.2-fold. Further enhanced AXIN1 binding and increases beta-catenin activity by 3.3-fold; when associated with A-1430. 1 Publication1
Mutagenesisi1430S → A: Enhanced AXIN1 binding. Further enhanced AXIN1 binding and increases beta-catenin activity by 3.3-fold; when associated with A-1420. 1 Publication1
Mutagenesisi1485L → A: No change in the phosphorylation state of PPPSP motif. Some reduction in Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1486N → A: No change in the phosphorylation state of PPPSP motif. Increased Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1487P → A: No change in the phosphorylation state of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1487P → C: No change in the phosphorylation state of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1488P → A: No change in the phosphorylation state of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1489P → A: No change in the phosphorylation state of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1490S → A: Greatly reduced phosphorylation of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1490S → T: Some loss of phosphorylation of PPPSP motif A. Little reduction in Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1491P → A: Greatly reduced phosphorylation of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1492A → G: No change in the phosphorylation state of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1493T → A: No change in the phosphorylation state of PPPSP motif A. Greatly reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1494E → A: No change in the phosphorylation state of PPPSP motif A. Little reduction of Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1495R → A: No change in the phosphorylation state of PPPSP motif. No reduction of Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1529T → A: No effect on the phosphorylation state of PPPSP motif B. 1 Publication1
Mutagenesisi1530T → A: Abolishes phosphorylation of PPPSP motif B. Reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1531P → A: Abolishes phosphorylation of PPPSP motif B. Reduced Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1572T → A: Abolishes Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1590S → A: Abolishes Wnt/beta-catenin signaling. 1 Publication1
Mutagenesisi1607S → A: Abolishes Wnt/beta-catenin signaling. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi4040.
MalaCardsiLRP6.
MIMi610947. phenotype.
616724. phenotype.
OpenTargetsiENSG00000070018.
ENSG00000281324.
Orphaneti94062. Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis.
PharmGKBiPA30456.

Polymorphism and mutation databases

BioMutaiLRP6.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19Sequence analysisAdd BLAST19
ChainiPRO_000001733020 – 1613Low-density lipoprotein receptor-related protein 6Add BLAST1594

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi42N-linked (GlcNAc...)Sequence analysis1
Glycosylationi81N-linked (GlcNAc...)Sequence analysis1
Glycosylationi281N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi286 ↔ 297PROSITE-ProRule annotation
Disulfide bondi293 ↔ 308PROSITE-ProRule annotation
Disulfide bondi310 ↔ 323PROSITE-ProRule annotation
Glycosylationi433N-linked (GlcNAc...)Sequence analysis1
Glycosylationi486N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi592 ↔ 603PROSITE-ProRule annotation
Disulfide bondi599 ↔ 612PROSITE-ProRule annotation
Disulfide bondi614 ↔ 627PROSITE-ProRule annotation
Glycosylationi692N-linked (GlcNAc...)1 Publication1
Glycosylationi859N-linked (GlcNAc...)1 Publication1
Glycosylationi865N-linked (GlcNAc...)1 Publication1
Disulfide bondi893 ↔ 904PROSITE-ProRule annotation1 Publication
Disulfide bondi900 ↔ 914PROSITE-ProRule annotation1 Publication
Disulfide bondi916 ↔ 929PROSITE-ProRule annotation1 Publication
Glycosylationi926N-linked (GlcNAc...)1 Publication1
Glycosylationi1039N-linked (GlcNAc...)1 Publication1
Disulfide bondi1207 ↔ 1218PROSITE-ProRule annotation1 Publication
Disulfide bondi1214 ↔ 1228PROSITE-ProRule annotation1 Publication
Disulfide bondi1230 ↔ 1243PROSITE-ProRule annotation1 Publication
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 cysteine1 Publication1
Lipidationi1399S-palmitoyl cysteine1 Publication1
Cross-linki1403Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei1420Phosphoserine; by CK11 Publication1
Modified residuei1430Phosphoserine; by CK11 Publication1
Modified residuei1479Phosphothreonine1 Publication1
Modified residuei1490Phosphoserine; by CDK14, GRK5 and GRK6Combined sources4 Publications1
Modified residuei1493Phosphothreonine; by CK11 Publication1

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-1479.10 Publications
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.
Palmitoylation on the two sites near the transmembrane domain leads to release of LRP6 from the endoplasmic reticulum.1 Publication
Mono-ubiquitinated which retains LRP6 in the endoplasmic reticulum. Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.2 Publications
N-glycosylation is required for cell surface location.2 Publications

Keywords - PTMi

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

Proteomic databases

EPDiO75581.
MaxQBiO75581.
PaxDbiO75581.
PeptideAtlasiO75581.
PRIDEiO75581.

PTM databases

iPTMnetiO75581.
PhosphoSitePlusiO75581.
SwissPalmiO75581.

Expressioni

Tissue specificityi

Widely coexpressed with LRP5 during embryogenesis and in adult tissues.

Inductioni

Decreased levels on WNT3A stimulation.1 Publication

Gene expression databases

BgeeiENSG00000070018.
CleanExiHS_LRP6.
ExpressionAtlasiO75581. baseline and differential.
GenevisibleiO75581. HS.

Organism-specific databases

HPAiCAB004490.
HPA029925.

Interactioni

Subunit structurei

Homodimer; disulfide-linked. Forms phosphorylated oligomer aggregates on Wnt-signaling. Forms a WNT-signaling complex formed of a WNT protein, a FZD protein and LRP5 or LRP6. 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 with C1orf187/DRAXIN; the interaction inhibits Wnt signaling (By similarity). Interacts (via the phosphorylated PPPSP motifs) with AXIN1; the interaction recruits the AXIN1/GSK3B complex to cell surface LRP6 signalsomes. Interacts with GRB10; the interaction prevents AXIN1 binding, thus negatively regulating the Wnt signaling pathway (By similarity). 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 with MESD; the interaction prevents the formation of LRP6 aggregates and targets LRP6 to the plasma membrane (By similarity). Interacts (via the cytoplasmic domain) with CSNKIE; the interaction phosphorylates LRP6, binds AXIN1 and inhibits AXIN1/GSK3B-mediated phosphorylation of beta-catenin. Interacts with MACF1. Interacts with DAB2; the interaction involves LRP6 phosphorylation by CK2 and sequesters LRP6 towards clathrin-mediated endocytosis. Interacts with TMEM198.By similarity15 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself2EBI-910915,EBI-910915
AMMECR1Q9Y4X05EBI-910915,EBI-8583355
ANTXR1Q9H6X23EBI-910915,EBI-905643
Axin1O356252EBI-910915,EBI-2365912From a different organism.
Axin1O7023912EBI-910915,EBI-6857773From a different organism.
CAV1Q031353EBI-910915,EBI-603614
DAB2P9808220EBI-910915,EBI-1171238
DKK1O949073EBI-910915,EBI-742864
Fzd8Q610914EBI-910915,EBI-6171689From a different organism.
GSK3AP498402EBI-910915,EBI-1044067
GSK3BP498414EBI-910915,EBI-373586
LRRK2Q5S0074EBI-910915,EBI-5323863
Mesdc1Q9ERE82EBI-910915,EBI-6985232From a different organism.
SOSTQ9BQB42EBI-910915,EBI-5746563
Wnt1P044262EBI-910915,EBI-1570911From a different organism.

GO - Molecular functioni

  • apolipoprotein binding Source: GO_Central
  • frizzled binding Source: BHF-UCL
  • protein homodimerization activity Source: BHF-UCL
  • receptor binding Source: BHF-UCL
  • Wnt-protein binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi110219. 43 interactors.
DIPiDIP-29884N.
IntActiO75581. 27 interactors.
MINTiMINT-3369849.
STRINGi9606.ENSP00000261349.

Structurei

Secondary structure

11613
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi22 – 26Combined sources5
Beta strandi28 – 35Combined sources8
Helixi36 – 38Combined sources3
Beta strandi44 – 59Combined sources16
Helixi60 – 62Combined sources3
Beta strandi64 – 69Combined sources6
Turni70 – 73Combined sources4
Beta strandi74 – 79Combined sources6
Beta strandi82 – 84Combined sources3
Beta strandi88 – 92Combined sources5
Beta strandi99 – 103Combined sources5
Turni104 – 107Combined sources4
Beta strandi108 – 113Combined sources6
Turni114 – 117Combined sources4
Beta strandi118 – 123Combined sources6
Beta strandi130 – 133Combined sources4
Beta strandi138 – 146Combined sources9
Helixi147 – 149Combined sources3
Beta strandi151 – 156Combined sources6
Beta strandi158 – 160Combined sources3
Beta strandi162 – 167Combined sources6
Beta strandi174 – 177Combined sources4
Beta strandi184 – 190Combined sources7
Turni191 – 194Combined sources4
Beta strandi195 – 200Combined sources6
Turni201 – 204Combined sources4
Beta strandi205 – 210Combined sources6
Beta strandi217 – 220Combined sources4
Beta strandi227 – 233Combined sources7
Beta strandi236 – 241Combined sources6
Turni242 – 245Combined sources4
Beta strandi246 – 251Combined sources6
Turni252 – 254Combined sources3
Beta strandi259 – 262Combined sources4
Beta strandi271 – 274Combined sources4
Helixi276 – 278Combined sources3
Turni285 – 289Combined sources5
Helixi290 – 292Combined sources3
Beta strandi294 – 299Combined sources6
Beta strandi305 – 309Combined sources5
Beta strandi328 – 337Combined sources10
Beta strandi339 – 346Combined sources8
Beta strandi360 – 368Combined sources9
Turni369 – 372Combined sources4
Beta strandi373 – 378Combined sources6
Turni379 – 382Combined sources4
Beta strandi383 – 388Combined sources6
Beta strandi389 – 391Combined sources3
Beta strandi395 – 398Combined sources4
Beta strandi407 – 411Combined sources5
Turni412 – 415Combined sources4
Beta strandi416 – 421Combined sources6
Turni422 – 425Combined sources4
Beta strandi426 – 431Combined sources6
Beta strandi438 – 441Combined sources4
Beta strandi447 – 454Combined sources8
Turni455 – 458Combined sources4
Beta strandi459 – 464Combined sources6
Beta strandi466 – 468Combined sources3
Beta strandi470 – 475Combined sources6
Beta strandi482 – 485Combined sources4
Beta strandi492 – 498Combined sources7
Turni499 – 502Combined sources4
Beta strandi503 – 508Combined sources6
Turni509 – 512Combined sources4
Beta strandi513 – 521Combined sources9
Beta strandi525 – 529Combined sources5
Beta strandi538 – 541Combined sources4
Beta strandi544 – 548Combined sources5
Beta strandi555 – 562Combined sources8
Beta strandi565 – 569Combined sources5
Beta strandi575 – 584Combined sources10
Helixi591 – 593Combined sources3
Helixi595 – 598Combined sources4
Beta strandi600 – 606Combined sources7
Beta strandi609 – 613Combined sources5
Beta strandi633 – 638Combined sources6
Beta strandi641 – 648Combined sources8
Beta strandi653 – 655Combined sources3
Beta strandi664 – 670Combined sources7
Turni671 – 674Combined sources4
Beta strandi675 – 680Combined sources6
Turni681 – 684Combined sources4
Beta strandi685 – 690Combined sources6
Beta strandi697 – 700Combined sources4
Beta strandi709 – 713Combined sources5
Turni714 – 717Combined sources4
Beta strandi718 – 723Combined sources6
Turni724 – 727Combined sources4
Beta strandi728 – 733Combined sources6
Beta strandi740 – 743Combined sources4
Beta strandi750 – 756Combined sources7
Turni757 – 760Combined sources4
Beta strandi761 – 766Combined sources6
Beta strandi768 – 770Combined sources3
Beta strandi772 – 777Combined sources6
Beta strandi784 – 787Combined sources4
Beta strandi791 – 799Combined sources9
Turni800 – 803Combined sources4
Beta strandi804 – 809Combined sources6
Turni810 – 813Combined sources4
Beta strandi814 – 819Combined sources6
Beta strandi826 – 830Combined sources5
Beta strandi835 – 841Combined sources7
Beta strandi844 – 849Combined sources6
Turni850 – 853Combined sources4
Beta strandi854 – 859Combined sources6
Turni860 – 862Combined sources3
Beta strandi867 – 870Combined sources4
Beta strandi878 – 882Combined sources5
Helixi884 – 886Combined sources3
Turni892 – 896Combined sources5
Helixi897 – 899Combined sources3
Beta strandi901 – 907Combined sources7
Turni908 – 910Combined sources3
Beta strandi911 – 915Combined sources5
Beta strandi933 – 940Combined sources8
Beta strandi943 – 947Combined sources5
Beta strandi967 – 973Combined sources7
Turni974 – 977Combined sources4
Beta strandi978 – 983Combined sources6
Turni984 – 987Combined sources4
Beta strandi988 – 993Combined sources6
Beta strandi1000 – 1003Combined sources4
Beta strandi1016 – 1022Combined sources7
Turni1023 – 1026Combined sources4
Beta strandi1027 – 1032Combined sources6
Turni1033 – 1036Combined sources4
Beta strandi1037 – 1042Combined sources6
Beta strandi1047 – 1052Combined sources6
Beta strandi1059 – 1065Combined sources7
Turni1066 – 1069Combined sources4
Beta strandi1070 – 1077Combined sources8
Beta strandi1080 – 1087Combined sources8
Beta strandi1094 – 1097Combined sources4
Beta strandi1104 – 1110Combined sources7
Turni1111 – 1114Combined sources4
Beta strandi1115 – 1120Combined sources6
Turni1121 – 1124Combined sources4
Beta strandi1125 – 1130Combined sources6
Beta strandi1137 – 1140Combined sources4
Beta strandi1147 – 1153Combined sources7
Beta strandi1156 – 1161Combined sources6
Turni1162 – 1165Combined sources4
Beta strandi1166 – 1171Combined sources6
Beta strandi1174 – 1176Combined sources3
Beta strandi1179 – 1182Combined sources4
Beta strandi1188 – 1194Combined sources7
Helixi1199 – 1204Combined sources6
Turni1206 – 1209Combined sources4
Helixi1210 – 1213Combined sources4
Beta strandi1215 – 1220Combined sources6
Turni1222 – 1224Combined sources3
Beta strandi1226 – 1229Combined sources4
Beta strandi1234 – 1236Combined sources3
Beta strandi1238 – 1241Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3S2KX-ray2.80A/B630-1246[»]
3S8VX-ray3.10A/B629-1243[»]
3S8ZX-ray2.80A629-1243[»]
3S94X-ray2.80A/B20-630[»]
3SOBX-ray1.90B20-335[»]
3SOQX-ray1.90A20-326[»]
3SOVX-ray1.27A20-326[»]
4A0PX-ray1.90A629-1244[»]
4DG6X-ray2.90A20-635[»]
4NM5X-ray2.30C1568-1575[»]
4NM7X-ray2.30C1603-1610[»]
5AIRX-ray2.53A/B1565-1575[»]
5FWWX-ray3.50A630-1246[»]
ProteinModelPortaliO75581.
SMRiO75581.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO75581.

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 – 236LDL-receptor class B 4Add BLAST43
Repeati237 – 276LDL-receptor class B 5Add BLAST40
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 – 584LDL-receptor class B 10Add BLAST42
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

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 DKK1.1 Publication
The PPPSP motifs play a central role in signal transduction by being phosphorylated, leading to activate the Wnt signaling pathway.1 Publication

Sequence similaritiesi

Belongs to the LDLR family.Curated
Contains 4 EGF-like domains.Curated
Contains 3 LDL-receptor class A domains.PROSITE-ProRule annotation
Contains 20 LDL-receptor class B repeats.PROSITE-ProRule annotation

Keywords - Domaini

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

Phylogenomic databases

eggNOGiENOG410IPT4. Eukaryota.
ENOG410XSY5. LUCA.
GeneTreeiENSGT00760000118968.
HOGENOMiHOG000230697.
HOVERGENiHBG049167.
InParanoidiO75581.
KOiK03068.
OMAiLLACSFC.
OrthoDBiEOG091G0178.
PhylomeDBiO75581.
TreeFamiTF315253.

Family and domain databases

Gene3Di2.120.10.30. 4 hits.
4.10.400.10. 3 hits.
InterProiIPR011042. 6-blade_b-propeller_TolB-like.
IPR000742. EGF-like_dom.
IPR023415. LDLR_class-A_CS.
IPR000033. LDLR_classB_rpt.
IPR002172. LDrepeatLR_classA_rpt.
IPR017049. LRP5/6.
[Graphical view]
PfamiPF00057. Ldl_recept_a. 3 hits.
PF00058. Ldl_recept_b. 11 hits.
[Graphical view]
PIRSFiPIRSF036314. LDL_recpt-rel_p5/6. 1 hit.
PRINTSiPR00261. LDLRECEPTOR.
SMARTiSM00181. EGF. 4 hits.
SM00192. LDLa. 3 hits.
SM00135. LY. 20 hits.
[Graphical view]
SUPFAMiSSF57424. SSF57424. 3 hits.
PROSITEiPS01186. EGF_2. 1 hit.
PS01209. LDLRA_1. 3 hits.
PS50068. LDLRA_2. 3 hits.
PS51120. LDLRB. 19 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

O75581-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGAVLRSLLA CSFCVLLRAA PLLLYANRRD LRLVDATNGK ENATIVVGGL
60 70 80 90 100
EDAAAVDFVF SHGLIYWSDV SEEAIKRTEF NKTESVQNVV VSGLLSPDGL
110 120 130 140 150
ACDWLGEKLY WTDSETNRIE VSNLDGSLRK VLFWQELDQP RAIALDPSSG
160 170 180 190 200
FMYWTDWGEV PKIERAGMDG SSRFIIINSE IYWPNGLTLD YEEQKLYWAD
210 220 230 240 250
AKLNFIHKSN LDGTNRQAVV KGSLPHPFAL TLFEDILYWT DWSTHSILAC
260 270 280 290 300
NKYTGEGLRE IHSDIFSPMD IHAFSQQRQP NATNPCGIDN GGCSHLCLMS
310 320 330 340 350
PVKPFYQCAC PTGVKLLENG 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
EGKIYWGDAK TDKIEVMNTD GTGRRVLVED KIPHIFGFTL LGDYVYWTDW
560 570 580 590 600
QRRSIERVHK RSAEREVIID QLPDLMGLKA TNVHRVIGSN PCAEENGGCS
610 620 630 640 650
HLCLYRPQGL RCACPIGFEL ISDMKTCIVP 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 DTNLIESSNM LGLNREVIAD DLPHPFGLTQ YQDYIYWTDW
860 870 880 890 900
SRRSIERANK TSGQNRTIIQ GHLDYVMDIL VFHSSRQSGW NECASSNGHC
910 920 930 940 950
SHLCLAVPVG GFVCGCPAHY SLNADNRTCS APTTFLLFSQ KSAINRMVID
960 970 980 990 1000
EQQSPDIILP IHSLRNVRAI DYDPLDKQLY WIDSRQNMIR KAQEDGSQGF
1010 1020 1030 1040 1050
TVVVSSVPSQ NLEIQPYDLS IDIYSRYIYW TCEATNVINV TRLDGRSVGV
1060 1070 1080 1090 1100
VLKGEQDRPR AVVVNPEKGY MYFTNLQERS PKIERAALDG TEREVLFFSG
1110 1120 1130 1140 1150
LSKPIALALD SRLGKLFWAD 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
PQQFTCFTGE IDCIPVAWRC DGFTECEDHS DELNCPVCSE SQFQCASGQC
1310 1320 1330 1340 1350
IDGALRCNGD ANCQDKSDEK NCEVLCLIDQ FRCANGQCIG KHKKCDHNVD
1360 1370 1380 1390 1400
CSDKSDELDC YPTEEPAPQA TNTVGSVIGV IVTIFVSGTV YFICQRMLCP
1410 1420 1430 1440 1450
RMKGDGETMT NDYVVHGPAS 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
ATAKGYTSDL NYDSEPVPPP PTPRSQYLSA EENYESCPPS PYTERSYSHH
1610
LYPPPPSPCT DSS
Length:1,613
Mass (Da):180,429
Last modified:January 11, 2011 - v2
Checksum:i413D2CF70A5D8B5C
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07620719A → V in STHAG7; impairs Wnt signaling; prevents transport to plasma membrane location. 1 Publication1
Natural variantiVAR_076208360R → H in ADCAD2. 1 PublicationCorresponds to variant rs141212743dbSNPEnsembl.1
Natural variantiVAR_076209433N → S in ADCAD2. 1 PublicationCorresponds to variant rs397515473dbSNPEnsembl.1
Natural variantiVAR_076210473R → Q in ADCAD2; impairs Wnt signaling. 1 PublicationCorresponds to variant rs397515474dbSNPEnsembl.1
Natural variantiVAR_030349483V → I.Corresponds to variant rs7975614dbSNPEnsembl.1
Natural variantiVAR_034701611R → C in ADCAD2; impairs Wnt signaling in vitro. 1 PublicationCorresponds to variant rs121918313dbSNPEnsembl.1
Natural variantiVAR_030350817S → C.Corresponds to variant rs2302686dbSNPEnsembl.1
Natural variantiVAR_0245201062V → I.1 PublicationCorresponds to variant rs2302685dbSNPEnsembl.1
Natural variantiVAR_0347021401R → H.Corresponds to variant rs34815107dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF074264 mRNA. Translation: AAC33006.1.
AC007537 Genomic DNA. No translation available.
AC007621 Genomic DNA. No translation available.
BC117136 mRNA. Translation: AAI17137.1.
BC126405 mRNA. Translation: AAI26406.1.
CCDSiCCDS8647.1.
PIRiJE0272.
RefSeqiNP_002327.2. NM_002336.2.
XP_006719141.1. XM_006719078.3.
UniGeneiHs.584775.
Hs.658913.

Genome annotation databases

EnsembliENST00000261349; ENSP00000261349; ENSG00000070018.
ENST00000628182; ENSP00000486315; ENSG00000281324.
GeneIDi4040.
KEGGihsa:4040.
UCSCiuc001rah.6. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF074264 mRNA. Translation: AAC33006.1.
AC007537 Genomic DNA. No translation available.
AC007621 Genomic DNA. No translation available.
BC117136 mRNA. Translation: AAI17137.1.
BC126405 mRNA. Translation: AAI26406.1.
CCDSiCCDS8647.1.
PIRiJE0272.
RefSeqiNP_002327.2. NM_002336.2.
XP_006719141.1. XM_006719078.3.
UniGeneiHs.584775.
Hs.658913.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3S2KX-ray2.80A/B630-1246[»]
3S8VX-ray3.10A/B629-1243[»]
3S8ZX-ray2.80A629-1243[»]
3S94X-ray2.80A/B20-630[»]
3SOBX-ray1.90B20-335[»]
3SOQX-ray1.90A20-326[»]
3SOVX-ray1.27A20-326[»]
4A0PX-ray1.90A629-1244[»]
4DG6X-ray2.90A20-635[»]
4NM5X-ray2.30C1568-1575[»]
4NM7X-ray2.30C1603-1610[»]
5AIRX-ray2.53A/B1565-1575[»]
5FWWX-ray3.50A630-1246[»]
ProteinModelPortaliO75581.
SMRiO75581.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110219. 43 interactors.
DIPiDIP-29884N.
IntActiO75581. 27 interactors.
MINTiMINT-3369849.
STRINGi9606.ENSP00000261349.

PTM databases

iPTMnetiO75581.
PhosphoSitePlusiO75581.
SwissPalmiO75581.

Polymorphism and mutation databases

BioMutaiLRP6.

Proteomic databases

EPDiO75581.
MaxQBiO75581.
PaxDbiO75581.
PeptideAtlasiO75581.
PRIDEiO75581.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000261349; ENSP00000261349; ENSG00000070018.
ENST00000628182; ENSP00000486315; ENSG00000281324.
GeneIDi4040.
KEGGihsa:4040.
UCSCiuc001rah.6. human.

Organism-specific databases

CTDi4040.
DisGeNETi4040.
GeneCardsiLRP6.
H-InvDBHIX0036693.
HGNCiHGNC:6698. LRP6.
HPAiCAB004490.
HPA029925.
MalaCardsiLRP6.
MIMi603507. gene.
610947. phenotype.
616724. phenotype.
neXtProtiNX_O75581.
OpenTargetsiENSG00000070018.
ENSG00000281324.
Orphaneti94062. Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis.
PharmGKBiPA30456.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IPT4. Eukaryota.
ENOG410XSY5. LUCA.
GeneTreeiENSGT00760000118968.
HOGENOMiHOG000230697.
HOVERGENiHBG049167.
InParanoidiO75581.
KOiK03068.
OMAiLLACSFC.
OrthoDBiEOG091G0178.
PhylomeDBiO75581.
TreeFamiTF315253.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000070018-MONOMER.
ReactomeiR-HSA-201681. TCF dependent signaling in response to WNT.
R-HSA-3772470. Negative regulation of TCF-dependent signaling by WNT ligand antagonists.
R-HSA-4641262. Disassembly of the destruction complex and recruitment of AXIN to the membrane.
R-HSA-4641263. Regulation of FZD by ubiquitination.
R-HSA-5340588. RNF mutants show enhanced WNT signaling and proliferation.
SignaLinkiO75581.
SIGNORiO75581.

Miscellaneous databases

ChiTaRSiLRP6. human.
EvolutionaryTraceiO75581.
GeneWikiiLRP6.
GenomeRNAii4040.
PROiO75581.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000070018.
CleanExiHS_LRP6.
ExpressionAtlasiO75581. baseline and differential.
GenevisibleiO75581. HS.

Family and domain databases

Gene3Di2.120.10.30. 4 hits.
4.10.400.10. 3 hits.
InterProiIPR011042. 6-blade_b-propeller_TolB-like.
IPR000742. EGF-like_dom.
IPR023415. LDLR_class-A_CS.
IPR000033. LDLR_classB_rpt.
IPR002172. LDrepeatLR_classA_rpt.
IPR017049. LRP5/6.
[Graphical view]
PfamiPF00057. Ldl_recept_a. 3 hits.
PF00058. Ldl_recept_b. 11 hits.
[Graphical view]
PIRSFiPIRSF036314. LDL_recpt-rel_p5/6. 1 hit.
PRINTSiPR00261. LDLRECEPTOR.
SMARTiSM00181. EGF. 4 hits.
SM00192. LDLa. 3 hits.
SM00135. LY. 20 hits.
[Graphical view]
SUPFAMiSSF57424. SSF57424. 3 hits.
PROSITEiPS01186. EGF_2. 1 hit.
PS01209. LDLRA_1. 3 hits.
PS50068. LDLRA_2. 3 hits.
PS51120. LDLRB. 19 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiLRP6_HUMAN
AccessioniPrimary (citable) accession number: O75581
Secondary accession number(s): Q17RZ2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 10, 2004
Last sequence update: January 11, 2011
Last modified: November 30, 2016
This is version 149 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. 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.