Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures
Basic Information
Protein Name :  Low-density lipoprotein receptor-related protein 6  

UniProtKB / Swiss-Prot ID :  LRP6_HUMAN

Gene Name (Synonyms) : 
LRP6  

Species :  Homo sapiens (Human). 

Subcellular Localization :  Membrane; Single-pass type I membrane protein. Endoplasmic reticulum. Note=On Wnt signaling, undergoes a cycle of caveolin- or clathrin-mediated endocytosis and plasma membrane location. Released from the endoplasmic reticulum on palmitoylation. Mono-ubi 

Protein Function :  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). 

Transmembrane Topology (topPTM) : LRP6_HUMAN 

Protein Sequence MGAVLRSLLACSFCVLLRAAPLLLYANRRDLRLVDATNGKENATIVVGGLEDAAAVDFVFSHGLIYWSDV...
Predicted Secondary Structure CHHHHHHHHHCCCCCCCCCCCEEEEECCCEEEEECCCCCCEEEEEEECCCCCEEEEEEEEECCEEEEEEC...
Protein Variant
LocationDescription
483V -> I (in dbSNP:rs7975614). VAR_030349
611R -> C (in ADCAD2; impairs Wnt signalingin vitro).
817S -> C (in dbSNP:rs2302686). VAR_030350
1062V -> I (in dbSNP:rs2302685). VAR_024520
1401R -> H (in dbSNP:rs34815107). VAR_034702
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Overview of Protein Modification Sites with Functional and Structural Information
Accessible Surface Area (ASA)
Pred. Secondary
Real Secondary
Disorder Prediction
Protein Domain
&
Experimental PTM Sites
Predicted PTM Sites
Protein Variant
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Experimental Post-Translational Modification Sites Download
Locations
Modification
Substrate Sites
&
Secondary Structure
Accessible Surface Area (%)
Resource
Reference
Structural Characterization
Orthologous
Protein Cluster
122PhosphoserineRIEVSNLDG
EEEEECCCC
20.91HPRD
Link-
127PhosphoserineNLDGSLRKV
CCCCCEEEE
25.35HPRD
Link-
692N-linked (GlcNAc...).RAFMNGSAL
EECCCCCCC
34.51UniProtKB
Link
859N-linked (GlcNAc...).IERANKTSG
EEEEECCCC
55.12UniProtKB
Link
865N-linked (GlcNAc...).TSGQNRTII
CCCCEEEEE
46.73UniProtKB
Link
926N-linked (GlcNAc...).LNADNRTCS
ECCCCCCCC
38.46UniProtKB
Link
977Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)DPLDKQLYW
EEECCEEEE
50.30Phosphositeplus
Link
1039N-linked (GlcNAc...).TNVINVTRL
CCEEEEEEC
25.48UniProtKB
Link
1394S-palmitoyl cysteine.VYFICQRML
CCEECCCCC
1.18UniProtKB
Link-
1399S-palmitoyl cysteine.QRMLCPRMK
CCCCCCCCC
1.15UniProtKB
Link-
1403Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin).CPRMKGDGE
CCCCCCCCC
55.95UniProtKB
Link-
1420Phosphoserine; by CK1.HGPASVPLG
CCCCCEECC
27.66UniProtKB
Link-
1430Phosphoserine; by CK1.VPHPSSLSG
CCCCCCCCC
40.66UniProtKB
Link-
1475PhosphoserineSSSSSTKGT
CCCCCCCCC
35.77Phosphositeplus
Link-
1476PhosphothreonineSSSSTKGTY
CCCCCCCCC
35.13Phosphositeplus
Link-
1479PhosphothreonineSTKGTYFPA
CCCCCCCCC
24.44Phosphositeplus
Link-
1479Phosphothreonine.STKGTYFPA
CCCCCCCCC
24.44UniProtKB
Link-
1480PhosphotyrosineTKGTYFPAI
CCCCCCCCC
19.08Phosphositeplus
Link-
1490PhosphoserineNPPPSPATE
CCCCCCCCC
32.70Phosphositeplus
Link-
1490Phosphoserine (GSK3B)NPPPSPATE
CCCCCCCCC
32.70HPRD
Link-
1490Phosphoserine; by CDK14, GRK5 and GRK6.NPPPSPATE
CCCCCCCCC
32.70UniProtKB
Link-
1493PhosphothreoninePSPATERSH
CCCCCCCCC
35.00Phosphositeplus
Link-
1493Phosphothreonine; by CK1.PSPATERSH
CCCCCCCCC
35.00UniProtKB
Link-
1515PhosphotyrosineTHRSYSYRP
CCCCCCCCC
15.07Phosphositeplus
Link-
1522PhosphotyrosineRPYSYRHFA
CCEECCCCC
11.41Phosphositeplus
Link-
1541PhosphotyrosineCDSDYAPSR
CCCCCCCCC
25.10Phosphositeplus
Link-
1544PhosphoserineDYAPSRRMT
CCCCCCCCC
25.09Phosphositeplus
Link-
1548PhosphothreonineSRRMTSVAT
CCCCCCCCC
20.45Phosphositeplus
Link-
1554Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)VATAKGYTS
CCCCCCCCC
48.36Phosphositeplus
Link-
1562PhosphotyrosineSDLNYDSEP
CCCCCCCCC
28.30Phosphositeplus
Link-
1572PhosphothreoninePPPPTPRSQ
CCCCCCCCC
36.79Phosphositeplus
Link-
1572Phosphothreonine (GSK3B)PPPPTPRSQ
CCCCCCCCC
36.79HPRD
Link-
1577PhosphotyrosinePRSQYLSAE
CCCCCCCCC
12.13Phosphositeplus
Link-
1607Phosphoserine (GSK3B)PPPPSPCTD
CCCCCCCCC
38.08HPRD
Link-
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Protein-Protein Interactions
      Interacting Protein      
Interaction type
Source ID
      Resource      
      Pubmed ID      
Domain-Domain Interactions
ANTR1_HUMANphysical interaction
physical interaction
physical interaction
EBI-910929
EBI-910937
EBI-910
intact16564009
16564009
16564009
ANTR2_HUMANphysical interaction
colocalization
EBI-910962
EBI-911003
intact16564009
16564009
LRP6_HUMANin vivoHPRD:04617HPRD12897152
AXN1_HUMANin vivoHPRD:04617HPRD12897152
FZD8_HUMANin vivoHPRD:04617HPRD11448771
11029007
WNT3A_HUMANin vivoHPRD:04617HPRD14739301
12897152
ANTR1_HUMANin vitro
in vivo
HPRD:04617HPRD16564009
ANTR2_HUMANin vitro
in vivo
HPRD:04617HPRD16564009
FGF20_HUMANENSP00000261349STRING
DKK4_HUMANENSP00000261349STRING
CCND1_HUMANENSP00000261349STRING
WISP1_HUMANENSP00000261349STRING
AXN1_HUMANENSP00000261349STRING
WNT3A_HUMANENSP00000261349STRING
DKK2_HUMANENSP00000261349STRING
FZD1_HUMANENSP00000261349STRING
WNT1_HUMANENSP00000261349STRING
SOST_HUMANENSP00000261349STRING
KREM2_HUMANENSP00000261349STRING
FZD4_HUMANENSP00000261349STRING
KC1E_HUMANENSP00000261349STRING
FZD5_HUMANENSP00000261349STRING
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Disease Reference
Kegg disease
OMIM disease
610947Coronary artery disease, autosomal dominant, 2 (ADCAD2)
Drug Reference
There are no disease associations of PTM sites.
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Related Literatures of Post-Translational Modification
N-linked Glycosylation
ReferencePubMed
"Structural basis of Wnt signaling inhibition by Dickkopf binding toLRP5/6.";
Ahn V.E., Chu M.L., Choi H.J., Tran D., Abo A., Weis W.I.;
Dev. Cell 21:862-873(2011).
Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 630-1246 IN COMPLEX WITHDKK1, SUBUNIT, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-692; ASN-859;ASN-865; ASN-926 AND ASN-1039.
Palmitoylation
ReferencePubMed
"Palmitoylation and ubiquitination regulate exit of the Wnt signalingprotein LRP6 from the endoplasmic reticulum.";
Abrami L., Kunz B., Iacovache I., van der Goot F.G.;
Proc. Natl. Acad. Sci. U.S.A. 105:5384-5389(2008).
Cited for: PALMITOYLATION AT CYS-1394 AND CYS-1399, UBIQUITINATION AT LYS-1403,SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-1394 AND CYS-1399.
Phosphorylation
ReferencePubMed
"Negative regulation of LRP6 function by casein kinase I epsilonphosphorylation.";
Swiatek W., Kang H., Garcia B.A., Shabanowitz J., Coombs G.S.,Hunt D.F., Virshup D.M.;
J. Biol. Chem. 281:12233-12241(2006).
Cited for: PHOSPHORYLATION AT SER-1420 AND SER-1430, FUNCTION, INTERACTION WITHCSNKIE AND AXIN1, MASS SPECTROMETRY, AND MUTAGENESIS OF SER-1420 ANDSER-1430.
"Analysis of endogenous LRP6 function reveals a novel feedbackmechanism by which Wnt negatively regulates its receptor.";
Khan Z., Vijayakumar S., de la Torre T.V., Rotolo S., Bafico A.;
Mol. Cell. Biol. 27:7291-7301(2007).
Cited for: GLYCOSYLATION, PHOSPHORYLATION AT SER-1490, INTERACTION WITH AXIN1,HOMODIMERIZATION, INDUCTION, AND SUBCELLULAR LOCATION.
"Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6phosphorylation.";
Bilic J., Huang Y.L., Davidson G., Zimmermann T., Cruciat C.M.,Bienz M., Niehrs C.;
Science 316:1619-1622(2007).
Cited for: PHOSPHORYLATION AT THR-1479, INTERACTION OF AXIN1, SUBUNIT, ANDSUBCELLULAR LOCATION.
"Cell cycle control of wnt receptor activation.";
Davidson G., Shen J., Huang Y.L., Su Y., Karaulanov E.,Bartscherer K., Hassler C., Stannek P., Boutros M., Niehrs C.;
Dev. Cell 17:788-799(2009).
Cited for: DOMAIN PPPSP MOTIF, AND PHOSPHORYLATION AT SER-1490.
"G Protein-coupled receptor kinases phosphorylate LRP6 in the Wntpathway.";
Chen M., Philipp M., Wang J., Premont R.T., Garrison T.R., Caron M.G.,Lefkowitz R.J., Chen W.;
J. Biol. Chem. 284:35040-35048(2009).
Cited for: PHOSPHORYLATION OF PPPSP MOTIFS, PHOSPHORYLATION AT SER-1490, ANDFUNCTION.
"A dual-kinase mechanism for Wnt co-receptor phosphorylation andactivation.";
Zeng X., Tamai K., Doble B., Li S., Huang H., Habas R., Okamura H.,Woodgett J., He X.;
Nature 438:873-877(2005).
Cited for: PHOSPHORYLATION OF PPPSP MOTIFS, PHOSPHORYLATION AT SER-1490 ANDTHR-1493, AND FUNCTION.
Ubiquitylation
ReferencePubMed
"Palmitoylation and ubiquitination regulate exit of the Wnt signalingprotein LRP6 from the endoplasmic reticulum.";
Abrami L., Kunz B., Iacovache I., van der Goot F.G.;
Proc. Natl. Acad. Sci. U.S.A. 105:5384-5389(2008).
Cited for: PALMITOYLATION AT CYS-1394 AND CYS-1399, UBIQUITINATION AT LYS-1403,SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-1394 AND CYS-1399.
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Basic Information | Overview of PTM Sites | Experimental PTM Sites | Protein-Protein Interactions | Drug and Disease Associations | Related Literatures