LRP6_HUMAN » Low-density lipoprotein receptor-related protein 6

LRP6_HUMAN » Low-density lipoprotein receptor-related protein 6
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
LRP6_HUMAN » Low-density lipoprotein receptor-related protein 6 » LRP-6;
Hydrophobic Thickness 25.6 ± 3.0 Å
Tilt Angle 1 ± 4°
ΔGtransfer -34.7 kcal/mol
ΔGfold -9.6 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC
Topology Out
TM Segments 1373-1395 (1373-1398)
Pathways

Wnt signaling pathway (KEGG)

PDB 3s94 (20-630), 4dg6 (20-635), 3s8z (629-1243), 4a0p (629-1244), 3s8v (A/B=629-1243), 3s2k (A/B=630-1246), 3soq (A=20-326), 3sov (A=20-326), 3sob (B=20-335), 4nm5 (C=1568-1575), 4nm7 (C=1603-1610)
OPM none
Complexes none
Interactions

ANTR1, Complex: ANTR1:LRP6, PubMed

ANTR2, Complex: ANTR2:LRP6, PubMed

BAMBI, Complex: BAMBI:LRP6, PubMed

PGFRB, Complex: LRP6:PGFRB, PubMed

ZNRF3, Complex: ZNRF3:LRP6, PubMed

Domains

AA: 107-147, PDBID: 3S94, Subunit B, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 150-191, PDBID: 3S94, Subunit B, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 194-234, PDBID: 3S94, Subunit B, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 286-323, PDBID: 3S94, Subunit A, Seq Identity:100%, Coagulation Factor Xa inhibitory site

AA: 372-412, PDBID: 3S94, Subunit B, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 415-455, PDBID: 3S94, Subunit B, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 458-499, PDBID: 3S94, Subunit B, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 592-627, PDBID: 3S94, Subunit A, Seq Identity:100%, Coagulation Factor Xa inhibitory site

AA: 674-714, PDBID: 3S2K, Subunit A, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 717-757, PDBID: 3S2K, Subunit A, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 760-800, PDBID: 3S2K, Subunit A, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 893-929, PDBID: 3S2K, Subunit A, Seq Identity:100%, Coagulation Factor Xa inhibitory site

AA: 1069-1111, PDBID: 3S2K, Subunit A, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 1114-1154, PDBID: 3S2K, Subunit A, Seq Identity:100%, Low-density lipoprotein receptor repeat class B

AA: 1207-1243, PDBID: 3S2K, Subunit A, Seq Identity:100%, Coagulation Factor Xa inhibitory site

AA: 1247-1285, PDBID: 1AJJ, Subunit A, Seq Identity:53%, Low-density lipoprotein receptor domain class A

AA: 1286-1322, PDBID: 1AJJ, Subunit A, Seq Identity:52%, Low-density lipoprotein receptor domain class A

AA: 1324-1360, PDBID: 2M0P, Subunit A, Seq Identity:50%, Low-density lipoprotein receptor domain class A

UniProt annotation for LRP6_HUMAN » Low-density lipoprotein receptor-related protein 6
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).

SUBUNIT: 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.

TISSUE SPECIFICITY: Widely coexpressed with LRP5 during embryogenesis and in adult tissues.

INDUCTION: Decreased levels on WNT3A stimulation.

DOMAIN: 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.

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

DISEASE: Coronary artery disease, autosomal dominant, 2 (ADCAD2) OMIM: A 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. disease is caused by mutations affecting the gene represented in this entry.

UniProt features for LRP6_HUMAN » Low-density lipoprotein receptor-related protein 6
SIGNAL 1 19 Potential.
CHAIN 20 1613 Low-density lipoprotein receptor-related protein 6.
REPEAT 63 106 LDL-receptor class B 1.
REPEAT 107 149 LDL-receptor class B 2.
REPEAT 150 193 LDL-receptor class B 3.
REPEAT 194 236 LDL-receptor class B 4.
REPEAT 237 276 LDL-receptor class B 5.
DOMAIN 282 324 EGF-like 1.
REPEAT 372 414 LDL-receptor class B 6.
REPEAT 415 457 LDL-receptor class B 7.
REPEAT 458 501 LDL-receptor class B 8.
REPEAT 502 542 LDL-receptor class B 9.
REPEAT 543 584 LDL-receptor class B 10.
DOMAIN 588 628 EGF-like 2.
REPEAT 674 716 LDL-receptor class B 11.
REPEAT 717 759 LDL-receptor class B 12.
REPEAT 760 802 LDL-receptor class B 13.
REPEAT 803 842 LDL-receptor class B 14.
REPEAT 843 885 LDL-receptor class B 15.
DOMAIN 889 930 EGF-like 3.
REPEAT 977 1025 LDL-receptor class B 16.
REPEAT 1026 1068 LDL-receptor class B 17.
REPEAT 1069 1113 LDL-receptor class B 18.
REPEAT 1114 1156 LDL-receptor class B 19.
REPEAT 1157 1198 LDL-receptor class B 20.
DOMAIN 1203 1244 EGF-like 4.
DOMAIN 1248 1286 LDL-receptor class A 1.
DOMAIN 1287 1323 LDL-receptor class A 2.
DOMAIN 1325 1361 LDL-receptor class A 3.
REGION 20 275 Beta-propeller 1.
REGION 328 589 Beta-propeller 2.
REGION 631 890 Beta-propeller 3.
REGION 933 1202 Beta-propeller 4.
MOTIF 1487 1493 PPPSP motif A.
MOTIF 1527 1534 PPPSP motif B.
MOTIF 1568 1575 PPPSP motif C.
MOTIF 1588 1593 PPPSP motif D.
MOTIF 1603 1610 PPPSP motif E.
DISULFID 286 297 By similarity.
DISULFID 293 308 By similarity.
DISULFID 310 323 By similarity.
DISULFID 592 603 By similarity.
DISULFID 599 612 By similarity.
DISULFID 614 627 By similarity.
DISULFID 893 904
DISULFID 900 914
DISULFID 916 929
DISULFID 1207 1218
DISULFID 1214 1228
DISULFID 1230 1243
DISULFID 1249 1263 By similarity.
DISULFID 1256 1276 By similarity.
DISULFID 1270 1285 By similarity.
DISULFID 1288 1300 By similarity.
DISULFID 1295 1313 By similarity.
DISULFID 1307 1322 By similarity.
DISULFID 1326 1338 By similarity.
DISULFID 1333 1351 By similarity.
DISULFID 1345 1360 By similarity.
CROSSLNK 1403 1403 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin).
Amino Acid Sequence for LRP6_HUMAN » Low-density lipoprotein receptor-related protein 6
MGAVLRSLLA CSFCVLLRAA PLLLYANRRD LRLVDATNGK ENATIVVGGL EDAAAVDFVF SHGLIYWSDV SEEAIKRTEF NKTESVQNVV VSGLLSPDGL ACDWLGEKLY WTDSETNRIE VSNLDGSLRK VLFWQELDQP RAIALDPSSG FMYWTDWGEV PKIERAGMDG SSRFIIINSE IYWPNGLTLD YEEQKLYWAD AKLNFIHKSN LDGTNRQAVV KGSLPHPFAL TLFEDILYWT DWSTHSILAC NKYTGEGLRE IHSDIFSPMD IHAFSQQRQP NATNPCGIDN GGCSHLCLMS PVKPFYQCAC PTGVKLLENG KTCKDGATEL LLLARRTDLR RISLDTPDFT DIVLQLEDIR HAIAIDYDPV EGYIYWTDDE VRAIRRSFID GSGSQFVVTA QIAHPDGIAV DWVARNLYWT DTGTDRIEVT RLNGTMRKIL ISEDLEEPRA IVLDPMVGYM YWTDWGEIPK IERAALDGSD RVVLVNTSLG WPNGLALDYD EGKIYWGDAK TDKIEVMNTD GTGRRVLVED KIPHIFGFTL LGDYVYWTDW QRRSIERVHK RSAEREVIID QLPDLMGLKA TNVHRVIGSN PCAEENGGCS HLCLYRPQGL RCACPIGFEL ISDMKTCIVP EAFLLFSRRA DIRRISLETN NNNVAIPLTG VKEASALDFD VTDNRIYWTD ISLKTISRAF MNGSALEHVV EFGLDYPEGM AVDWLGKNLY WADTGTNRIE VSKLDGQHRQ VLVWKDLDSP RALALDPAEG FMYWTEWGGK PKIDRAAMDG SERTTLVPNV GRANGLTIDY AKRRLYWTDL DTNLIESSNM LGLNREVIAD DLPHPFGLTQ YQDYIYWTDW SRRSIERANK TSGQNRTIIQ GHLDYVMDIL VFHSSRQSGW NECASSNGHC SHLCLAVPVG GFVCGCPAHY SLNADNRTCS APTTFLLFSQ KSAINRMVID EQQSPDIILP IHSLRNVRAI DYDPLDKQLY WIDSRQNMIR KAQEDGSQGF TVVVSSVPSQ NLEIQPYDLS IDIYSRYIYW TCEATNVINV TRLDGRSVGV VLKGEQDRPR AIVVNPEKGY MYFTNLQERS PKIERAALDG TEREVLFFSG LSKPIALALD SRLGKLFWAD SDLRRIESSD LSGANRIVLE DSNILQPVGL TVFENWLYWI DKQQQMIEKI DMTGREGRTK VQARIAQLSD IHAVKELNLQ EYRQHPCAQD NGGCSHICLV KGDGTTRCSC PMHLVLLQDE LSCGEPPTCS PQQFTCFTGE IDCIPVAWRC DGFTECEDHS DELNCPVCSE SQFQCASGQC IDGALRCNGD ANCQDKSDEK NCEVLCLIDQ FRCANGQCIG KHKKCDHNVD CSDKSDELDC YPTEEPAPQA TNTVGSVIGV IVTIFVSGTV YFICQRMLCP RMKGDGETMT NDYVVHGPAS VPLGYVPHPS SLSGSLPGMS RGKSMISSLS IMGGSSGPPY DRAHVTGASS SSSSSTKGTY FPAILNPPPS PATERSHYTM EFGYSSNSPS THRSYSYRPY SYRHFAPPTT PCSTDVCDSD YAPSRRMTSV ATAKGYTSDL NYDSEPVPPP PTPRSQYLSA EENYESCPPS PYTERSYSHH LYPPPPSPCT DSS