ID LRP4_HUMAN Reviewed; 1905 AA. AC O75096; B2RN39; Q4AC85; Q5KTZ5; DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot. DT 24-NOV-2009, sequence version 4. DT 13-JUN-2012, entry version 103. DE RecName: Full=Low-density lipoprotein receptor-related protein 4; DE Short=LRP-4; DE AltName: Full=Multiple epidermal growth factor-like domains 7; DE Flags: Precursor; GN Name=LRP4; Synonyms=KIAA0816, LRP10, MEGF7; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS VAL-1086; GLY-1554 AND RP GLN-1646. RC TISSUE=Brain; RA Ishikawa K., Fujimoto H., Kim D., Saeki S.; RT "Low density lipoprotein receptor-related protein 10."; RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS VAL-1086; RP GLY-1554 AND GLN-1646. RC TISSUE=Brain; RX MEDLINE=98360089; PubMed=9693030; DOI=10.1006/geno.1998.5341; RA Nakayama M., Nakajima D., Nagase T., Nomura N., Seki N., Ohara O.; RT "Identification of high-molecular-weight proteins with multiple EGF- RT like motifs by motif-trap screening."; RL Genomics 51:27-34(1998). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S., RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., RA Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS VAL-1086; RP GLY-1554 AND GLN-1646. RC TISSUE=Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION IN THE REGULATION OF CANONICAL WTN SIGNALING, VARIANTS CLSS RP ASN-137; TYR-160; ASN-449; PRO-461; PHE-473; ASN-529 AND ARG-1017, AND RP CHARACTERIZATION OF VARIANTS CLSS ASN-137; TYR-160; ASN-449; PHE-473 RP AND ASN-529. RX PubMed=20381006; DOI=10.1016/j.ajhg.2010.03.004; RA Li Y., Pawlik B., Elcioglu N., Aglan M., Kayserili H., Yigit G., RA Percin F., Goodman F., Nurnberg G., Cenani A., Urquhart J., RA Chung B.D., Ismail S., Amr K., Aslanger A.D., Becker C., Netzer C., RA Scambler P., Eyaid W., Hamamy H., Clayton-Smith J., Hennekam R., RA Nurnberg P., Herz J., Temtamy S.A., Wollnik B.; RT "LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and RT kidney malformations in Cenani-Lenz syndrome."; RL Am. J. Hum. Genet. 86:696-706(2010). RN [6] RP FUNCTION, INTERACTION WITH SOST, TISSUE SPECIFICITY, MASS RP SPECTROMETRY, VARIANTS SOST2 TRP-1170 AND SER-1186, AND RP CHARACTERIZATION OF VARIANTS SOST2 TRP-1170 AND SER-1186. RX PubMed=21471202; DOI=10.1074/jbc.M110.190330; RA Leupin O., Piters E., Halleux C., Hu S., Kramer I., Morvan F., RA Bouwmeester T., Schirle M., Bueno-Lozano M., Fuentes F.J., Itin P.H., RA Boudin E., de Freitas F., Jennes K., Brannetti B., Charara N., RA Ebersbach H., Geisse S., Lu C.X., Bauer A., Van Hul W., Kneissel M.; RT "Bone overgrowth-associated mutations in the LRP4 gene impair RT sclerostin facilitator function."; RL J. Biol. Chem. 286:19489-19500(2011). CC -!- FUNCTION: Mediates SOST-dependent inhibition of bone formation. CC Functions as a specific facilitator of SOST-mediated inhibition of CC Wnt signaling. Plays a key role in the formation and the CC maintenance of the neuromuscular junction (NMJ), the synapse CC between motor neuron and skeletal muscle. Directly binds AGRIN and CC recruits it to the MUSK signaling complex. Mediates the AGRIN- CC induced phosphorylation of MUSK, the kinase of the complex. The CC activation of MUSK in myotubes induces the formation of NMJ by CC regulating different processes including the transcription of CC specific genes and the clustering of AChR in the postsynaptic CC membrane. Alternatively, may be involved in the negative CC regulation of the canonical Wnt signaling pathway, being able to CC antagonize the LRP6-mediated activation of this pathway. More CC generally, has been proposed to function as a cell surface CC endocytic receptor binding and internalizing extracellular ligands CC for degradation by lysosomes. CC -!- SUBUNIT: Homooligomer. Interacts with MUSK; the heterodimer forms CC an AGRIN receptor complex that binds AGRIN resulting in activation CC of MUSK (By similarity). Interacts (via the extracellular domain) CC with SOST; the interaction facilitates the inhibition of Wnt CC signaling. CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane CC protein (Potential). CC -!- TISSUE SPECIFICITY: Expressed in bone; present in osteoblasts and CC osteocytes. No expression is observed in osteoclast. Expressed in CC several regions of the brain. CC -!- DISEASE: Defects in LRP4 are the cause of Cenani-Lenz syndactyly CC syndrome (CLSS) [MIM:212780]. It is a congenital malformation CC syndrome defined as complete and complex syndactyly of the hands CC combined with malformations of the forearm bones and similar CC manifestations in the lower limbs. CC -!- DISEASE: Defects in LRP4 are the cause of sclerosteosis type 2 CC (SOST2) [MIM:614305]. A sclerosing bone dysplasia characterized by CC a generalized hyperostosis and sclerosis leading to a markedly CC thickened skull, with mandible, ribs, clavicles and all long bones CC also being affected. Due to narrowing of the foramina of the CC cranial nerves, facial nerve palsy, hearing loss and atrophy of CC the optic nerves can occur. Sclerosteosis is clinically and CC radiologically very similar to van Buchem disease, mainly CC differentiated by hand malformations and a large stature in CC sclerosteosis patients. CC -!- SIMILARITY: Belongs to the LDLR family. CC -!- SIMILARITY: Contains 3 EGF-like domains. CC -!- SIMILARITY: Contains 8 LDL-receptor class A domains. CC -!- SIMILARITY: Contains 20 LDL-receptor class B repeats. CC -!- SEQUENCE CAUTION: CC Sequence=BAE19679.1; Type=Erroneous initiation; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB084910; BAD83615.1; -; mRNA. DR EMBL; AB011540; BAA32468.1; -; mRNA. DR EMBL; AB231861; BAE19679.1; ALT_INIT; mRNA. DR EMBL; AC021573; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC037360; AAH37360.1; -; mRNA. DR EMBL; BC041048; AAH41048.1; -; mRNA. DR EMBL; BC136667; AAI36668.1; -; mRNA. DR EMBL; BC136668; AAI36669.1; -; mRNA. DR IPI; IPI00930747; -. DR RefSeq; NP_002325.2; NM_002334.3. DR UniGene; Hs.4930; -. DR ProteinModelPortal; O75096; -. DR SMR; O75096; 25-1650. DR IntAct; O75096; 3. DR STRING; O75096; -. DR PhosphoSite; O75096; -. DR PRIDE; O75096; -. DR Ensembl; ENST00000378623; ENSP00000367888; ENSG00000134569. DR GeneID; 4038; -. DR KEGG; hsa:4038; -. DR UCSC; uc001ndn.4; human. DR CTD; 4038; -. DR GeneCards; GC11M046834; -. DR H-InvDB; HIX0009607; -. DR HGNC; HGNC:6696; LRP4. DR HPA; HPA011934; -. DR HPA; HPA012300; -. DR MIM; 212780; phenotype. DR MIM; 604270; gene. DR MIM; 614305; phenotype. DR neXtProt; NX_O75096; -. DR Orphanet; 3258; Cenani-Lenz syndrome. DR PharmGKB; PA30454; -. DR eggNOG; NOG235850; -. DR GeneTree; ENSGT00650000093259; -. DR HOGENOM; HOG000047507; -. DR HOVERGEN; HBG049163; -. DR InParanoid; O75096; -. DR OrthoDB; EOG405S05; -. DR NextBio; 15818; -. DR ArrayExpress; O75096; -. DR Bgee; O75096; -. DR CleanEx; HS_LRP4; -. DR Genevestigator; O75096; -. DR GermOnline; ENSG00000134569; Homo sapiens. DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW. DR GO; GO:0005509; F:calcium ion binding; NAS:UniProtKB. DR GO; GO:0004872; F:receptor activity; IEA:UniProtKB-KW. DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW. DR GO; GO:0090090; P:negative regulation of canonical Wnt receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030279; P:negative regulation of ossification; IMP:UniProtKB. DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW. DR Gene3D; G3DSA:2.120.10.30; 6-blade_b-propeller_TolB-like; 4. DR Gene3D; G3DSA:4.10.400.10; LDL_rcpt_classA_cys-rich; 8. DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like. DR InterPro; IPR006210; EGF-like. DR InterPro; IPR001881; EGF-like_Ca-bd. DR InterPro; IPR013032; EGF-like_reg_CS. DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site. DR InterPro; IPR018097; EGF_Ca-bd_CS. DR InterPro; IPR009030; Growth_fac_rcpt. DR InterPro; IPR023415; LDLR_class-A_CS. DR InterPro; IPR000033; LDLR_classB_rpt. DR InterPro; IPR002172; LDrepeatLR_classA_rpt. DR Pfam; PF00057; Ldl_recept_a; 8. DR Pfam; PF00058; Ldl_recept_b; 16. DR SMART; SM00181; EGF; 4. DR SMART; SM00179; EGF_CA; 1. DR SMART; SM00192; LDLa; 8. DR SMART; SM00135; LY; 20. DR SUPFAM; SSF57184; Grow_fac_recept; 1. DR SUPFAM; SSF57424; LDL_rcpt_classA_cys-rich; 8. DR PROSITE; PS00010; ASX_HYDROXYL; 1. DR PROSITE; PS00022; EGF_1; FALSE_NEG. DR PROSITE; PS01186; EGF_2; 3. DR PROSITE; PS50026; EGF_3; FALSE_NEG. DR PROSITE; PS01187; EGF_CA; 1. DR PROSITE; PS01209; LDLRA_1; 8. DR PROSITE; PS50068; LDLRA_2; 8. DR PROSITE; PS51120; LDLRB; 20. PE 1: Evidence at protein level; KW Calcium; Complete proteome; Developmental protein; Differentiation; KW Disease mutation; Disulfide bond; EGF-like domain; Endocytosis; KW Glycoprotein; Membrane; Phosphoprotein; Polymorphism; Receptor; KW Reference proteome; Repeat; Signal; Transmembrane; KW Transmembrane helix; Wnt signaling pathway. FT SIGNAL 1 20 Potential. FT CHAIN 21 1905 Low-density lipoprotein receptor-related FT protein 4. FT /FTId=PRO_0000017325. FT TOPO_DOM 21 1725 Extracellular (Potential). FT TRANSMEM 1726 1746 Helical; (Potential). FT TOPO_DOM 1747 1905 Cytoplasmic (Potential). FT DOMAIN 26 67 LDL-receptor class A 1. FT DOMAIN 70 106 LDL-receptor class A 2. FT DOMAIN 109 144 LDL-receptor class A 3. FT DOMAIN 147 183 LDL-receptor class A 4. FT DOMAIN 190 226 LDL-receptor class A 5. FT DOMAIN 230 266 LDL-receptor class A 6. FT DOMAIN 269 305 LDL-receptor class A 7. FT DOMAIN 311 350 LDL-receptor class A 8. FT DOMAIN 354 394 EGF-like 1; calcium-binding (Potential). FT DOMAIN 395 434 EGF-like 2; calcium-binding (Potential). FT REPEAT 480 522 LDL-receptor class B 1. FT REPEAT 523 565 LDL-receptor class B 2. FT REPEAT 566 609 LDL-receptor class B 3. FT REPEAT 610 652 LDL-receptor class B 4. FT REPEAT 653 693 LDL-receptor class B 5. FT DOMAIN 698 737 EGF-like 3. FT REPEAT 785 827 LDL-receptor class B 6. FT REPEAT 828 870 LDL-receptor class B 7. FT REPEAT 871 914 LDL-receptor class B 8. FT REPEAT 915 956 LDL-receptor class B 9. FT REPEAT 957 998 LDL-receptor class B 10. FT REPEAT 1093 1135 LDL-receptor class B 11. FT REPEAT 1136 1178 LDL-receptor class B 12. FT REPEAT 1179 1222 LDL-receptor class B 13. FT REPEAT 1223 1263 LDL-receptor class B 14. FT REPEAT 1264 1306 LDL-receptor class B 15. FT REPEAT 1397 1439 LDL-receptor class B 16. FT REPEAT 1440 1482 LDL-receptor class B 17. FT REPEAT 1483 1526 LDL-receptor class B 18. FT REPEAT 1527 1568 LDL-receptor class B 19. FT REPEAT 1569 1610 LDL-receptor class B 20. FT MOTIF 1766 1769 Endocytosis signal (Potential). FT MOD_RES 1887 1887 Phosphoserine (By similarity). FT CARBOHYD 264 264 N-linked (GlcNAc...) (Potential). FT CARBOHYD 498 498 N-linked (GlcNAc...) (Potential). FT CARBOHYD 719 719 N-linked (GlcNAc...) (Potential). FT CARBOHYD 901 901 N-linked (GlcNAc...) (Potential). FT CARBOHYD 1077 1077 N-linked (GlcNAc...) (Potential). FT CARBOHYD 1415 1415 N-linked (GlcNAc...) (Potential). FT CARBOHYD 1467 1467 N-linked (GlcNAc...) (Potential). FT DISULFID 27 44 By similarity. FT DISULFID 34 57 By similarity. FT DISULFID 51 66 By similarity. FT DISULFID 71 83 By similarity. FT DISULFID 78 96 By similarity. FT DISULFID 90 105 By similarity. FT DISULFID 110 122 By similarity. FT DISULFID 117 135 By similarity. FT DISULFID 129 143 By similarity. FT DISULFID 148 160 By similarity. FT DISULFID 155 173 By similarity. FT DISULFID 167 182 By similarity. FT DISULFID 191 203 By similarity. FT DISULFID 198 216 By similarity. FT DISULFID 210 225 By similarity. FT DISULFID 231 243 By similarity. FT DISULFID 238 256 By similarity. FT DISULFID 250 265 By similarity. FT DISULFID 270 282 By similarity. FT DISULFID 277 295 By similarity. FT DISULFID 289 304 By similarity. FT DISULFID 312 324 By similarity. FT DISULFID 319 337 By similarity. FT DISULFID 331 349 By similarity. FT DISULFID 358 369 By similarity. FT DISULFID 365 378 By similarity. FT DISULFID 380 393 By similarity. FT DISULFID 399 409 By similarity. FT DISULFID 405 418 By similarity. FT DISULFID 420 433 By similarity. FT DISULFID 702 713 By similarity. FT DISULFID 709 722 By similarity. FT DISULFID 724 736 By similarity. FT VARIANT 137 137 D -> N (in CLSS; abolishes the FT antagonistic effect of LRP4 on LRP6- FT mediated activation of Wnt signaling). FT /FTId=VAR_063776. FT VARIANT 160 160 C -> Y (in CLSS; abolishes the FT antagonistic effect of LRP4 on LRP6- FT mediated activation of Wnt signaling). FT /FTId=VAR_063777. FT VARIANT 314 314 L -> S (in dbSNP:rs7926667). FT /FTId=VAR_058290. FT VARIANT 449 449 D -> N (in CLSS; abolishes the FT antagonistic effect of LRP4 on LRP6- FT mediated activation of Wnt signaling). FT /FTId=VAR_063778. FT VARIANT 461 461 T -> P (in CLSS). FT /FTId=VAR_063779. FT VARIANT 473 473 L -> F (in CLSS; abolishes the FT antagonistic effect of LRP4 on LRP6- FT mediated activation of Wnt signaling). FT /FTId=VAR_063780. FT VARIANT 529 529 D -> N (in CLSS; abolishes the FT antagonistic effect of LRP4 on LRP6- FT mediated activation of Wnt signaling). FT /FTId=VAR_063781. FT VARIANT 1017 1017 C -> R (in CLSS). FT /FTId=VAR_063782. FT VARIANT 1086 1086 I -> V (in dbSNP:rs6485702). FT /FTId=VAR_057955. FT VARIANT 1170 1170 R -> W (in SOST2; impairs the interaction FT with SOST; loss of function as FT facilitator of SOST-mediated inhibition FT of Wnt signaling). FT /FTId=VAR_066630. FT VARIANT 1186 1186 W -> S (in SOST2; impairs the interaction FT with SOST; loss of function as FT facilitator of SOST-mediated inhibition FT of Wnt signaling). FT /FTId=VAR_066631. FT VARIANT 1203 1203 A -> V (in dbSNP:rs2306033). FT /FTId=VAR_058291. FT VARIANT 1238 1238 A -> T (in dbSNP:rs2306031). FT /FTId=VAR_058292. FT VARIANT 1554 1554 S -> G (in dbSNP:rs2306029). FT /FTId=VAR_057956. FT VARIANT 1646 1646 R -> Q (in dbSNP:rs3816614). FT /FTId=VAR_057957. FT CONFLICT 1472 1475 EPRA -> D (in Ref. 2; BAE19679). FT CONFLICT 1478 1478 V -> A (in Ref. 2; BAE19679). FT CONFLICT 1862 1862 T -> M (in Ref. 1; BAD83615 and 2; FT BAA32468). SQ SEQUENCE 1905 AA; 212045 MW; A39117C18279F9AA CRC64; MRRQWGALLL GALLCAHGLA SSPECACGRS HFTCAVSALG ECTCIPAQWQ CDGDNDCGDH SDEDGCILPT CSPLDFHCDN GKCIRRSWVC DGDNDCEDDS DEQDCPPREC EEDEFPCQNG YCIRSLWHCD GDNDCGDNSD EQCDMRKCSD KEFRCSDGSC IAEHWYCDGD TDCKDGSDEE NCPSAVPAPP CNLEEFQCAY GRCILDIYHC DGDDDCGDWS DESDCSSHQP CRSGEFMCDS GLCINAGWRC DGDADCDDQS DERNCTTSMC TAEQFRCHSG RCVRLSWRCD GEDDCADNSD EENCENTGSP QCALDQFLCW NGRCIGQRKL CNGVNDCGDN SDESPQQNCR PRTGEENCNV NNGGCAQKCQ MVRGAVQCTC HTGYRLTEDG HTCQDVNECA EEGYCSQGCT NSEGAFQCWC ETGYELRPDR RSCKALGPEP VLLFANRIDI RQVLPHRSEY TLLLNNLENA IALDFHHRRE LVFWSDVTLD RILRANLNGS NVEEVVSTGL ESPGGLAVDW VHDKLYWTDS GTSRIEVANL DGAHRKVLLW QNLEKPRAIA LHPMEGTIYW TDWGNTPRIE ASSMDGSGRR IIADTHLFWP NGLTIDYAGR RMYWVDAKHH VIERANLDGS HRKAVISQGL PHPFAITVFE DSLYWTDWHT KSINSANKFT GKNQEIIRNK LHFPMDIHTL HPQRQPAGKN RCGDNNGGCT HLCLPSGQNY TCACPTGFRK ISSHACAQSL DKFLLFARRM DIRRISFDTE DLSDDVIPLA DVRSAVALDW DSRDDHVYWT DVSTDTISRA KWDGTGQEVV VDTSLESPAG LAIDWVTNKL YWTDAGTDRI EVANTDGSMR TVLIWENLDR PRDIVVEPMG GYMYWTDWGA SPKIERAGMD ASGRQVIISS NLTWPNGLAI DYGSQRLYWA DAGMKTIEFA GLDGSKRKVL IGSQLPHPFG LTLYGERIYW TDWQTKSIQS ADRLTGLDRE TLQENLENLM DIHVFHRRRP PVSTPCAMEN GGCSHLCLRS PNPSGFSCTC PTGINLLSDG KTCSPGMNSF LIFARRIDIR MVSLDIPYFA DVVVPINITM KNTIAIGVDP QEGKVYWSDS TLHRISRANL DGSQHEDIIT TGLQTTDGLA VDAIGRKVYW TDTGTNRIEV GNLDGSMRKV LVWQNLDSPR AIVLYHEMGF MYWTDWGENA KLERSGMDGS DRAVLINNNL GWPNGLTVDK ASSQLLWADA HTERIEAADL NGANRHTLVS PVQHPYGLTL LDSYIYWTDW QTRSIHRADK GTGSNVILVR SNLPGLMDMQ AVDRAQPLGF NKCGSRNGGC SHLCLPRPSG FSCACPTGIQ LKGDGKTCDP SPETYLLFSS RGSIRRISLD TSDHTDVHVP VPELNNVISL DYDSVDGKVY YTDVFLDVIR RADLNGSNME TVIGRGLKTT DGLAVDWVAR NLYWTDTGRN TIEASRLDGS CRKVLINNSL DEPRAIAVFP RKGYLFWTDW GHIAKIERAN LDGSERKVLI NTDLGWPNGL TLDYDTRRIY WVDAHLDRIE SADLNGKLRQ VLVSHVSHPF ALTQQDRWIY WTDWQTKSIQ RVDKYSGRNK ETVLANVEGL MDIIVVSPQR QTGTNACGVN NGGCTHLCFA RASDFVCACP DEPDSRPCSL VPGLVPPAPR ATGMSEKSPV LPNTPPTTLY SSTTRTRTSL EEVEGRCSER DARLGLCARS NDAVPAAPGE GLHISYAIGG LLSILLILVV IAALMLYRHK KSKFTDPGMG NLTYSNPSYR TSTQEVKIEA IPKPAMYNQL CYKKEGGPDH NYTKEKIKIV EGICLLSGDD AEWDDLKQLR SSRGGLLRDH VCMKTDTVSI QASSGSLDDT ETEQLLQEEQ SECSSVHTAA TPERRGSLPD TGWKHERKLS SESQV //