LRP5_HUMAN » Low-density lipoprotein receptor-related protein 5

LRP5_HUMAN » Low-density lipoprotein receptor-related protein 5
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
LRP5_HUMAN » Low-density lipoprotein receptor-related protein 5 » LRP-5;
Hydrophobic Thickness 36.0 ± 3.0 Å
Tilt Angle 1 ± 1°
ΔGtransfer -42.8 kcal/mol
ΔGfold -10.9 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 1382-1407 (1379-1409)
Pathways

Wnt signaling pathway (KEGG)

PDB none
OPM none
Complexes none
Interactions

APCD1, Complex: LRP5:APCD1, PubMed

Domains

AA: 120-160, PDBID: 3S94, Subunit B, Seq Identity:84%, Low-density lipoprotein receptor repeat class B

AA: 163-204, PDBID: 3S94, Subunit B, Seq Identity:75%, Low-density lipoprotein receptor repeat class B

AA: 207-245, PDBID: 3S94, Subunit B, Seq Identity:77%, Low-density lipoprotein receptor repeat class B

AA: 299-336, PDBID: 3S94, Subunit A, Seq Identity:74%, Coagulation Factor Xa inhibitory site

AA: 385-425, PDBID: 3S94, Subunit B, Seq Identity:72%, Low-density lipoprotein receptor repeat class B

AA: 428-468, PDBID: 3S94, Subunit B, Seq Identity:88%, Low-density lipoprotein receptor repeat class B

AA: 471-512, PDBID: 3S94, Subunit B, Seq Identity:77%, Low-density lipoprotein receptor repeat class B

AA: 515-552, PDBID: 1NPE, Subunit A, Seq Identity:37%, Low-density lipoprotein receptor repeat class B

AA: 605-640, PDBID: 3S94, Subunit A, Seq Identity:70%, Coagulation Factor Xa inhibitory site

AA: 687-727, PDBID: 3S2K, Subunit A, Seq Identity:90%, Low-density lipoprotein receptor repeat class B

AA: 730-770, PDBID: 3S2K, Subunit A, Seq Identity:86%, Low-density lipoprotein receptor repeat class B

AA: 773-813, PDBID: 3S2K, Subunit A, Seq Identity:72%, Low-density lipoprotein receptor repeat class B

AA: 816-852, PDBID: 3S94, Subunit B, Seq Identity:47%, Low-density lipoprotein receptor repeat class B

AA: 856-896, PDBID: 1NPE, Subunit A, Seq Identity:26%, Low-density lipoprotein receptor repeat class B

AA: 906-941, PDBID: 3S2K, Subunit A, Seq Identity:50%, Coagulation Factor Xa inhibitory site

AA: 1124-1162, PDBID: 3S2K, Subunit A, Seq Identity:72%, Low-density lipoprotein receptor repeat class B

AA: 1257-1295, PDBID: 1AJJ, Subunit A, Seq Identity:56%, Low-density lipoprotein receptor domain class A

AA: 1296-1332, PDBID: 2I1P, Subunit A, Seq Identity:56%, Low-density lipoprotein receptor domain class A

AA: 1334-1370, PDBID: 2FYJ, Subunit A, Seq Identity:51%, Low-density lipoprotein receptor domain class A

UniProt annotation for LRP5_HUMAN » Low-density lipoprotein receptor-related protein 5
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. Appears be required for postnatal control of vascular regression in the eye. Required for posterior patterning of the epiblast during gastrulation.

SUBUNIT: Homodimer; disulfide-linked. Forms phosphorylated oligomer aggregates on Wnt-signaling (By similarity). Component of a Wnt-signaling complex that contains a WNT protein, a FZD protein and LRP5 or LRP6. Interacts with FZD8; the interaction is formed on WNT-binding and signaling. Interacts (via the phosphorylated PPPSP motif domains) with AXIN1; the interaction prevents inhibition of beta-catenin phosphorylation and signaling and is enhanced in the presence of GSK3B and WNT1 or WNT3A. Interacts (via beta-propeller regions 3 and 4) with DKK1; the interaction, enhanced by MESD and/or KREMEN, inhibits beta-catenin signaling by preventing GSK3-mediated phosphorylation of the PPPSP motifs and subsequent, AXIN1 binding. Interacts with MESD; the interaction prevents the formation of LRP5 aggregates, targets LRP5 to the plasma membrane and, when complexed with KREMEN2, increases DKK1 binding. Interacts with CSNK1E. Interacts with SOST; the interaction antagonizes canonical Wnt signaling. Interacts with APCDD1.

TISSUE SPECIFICITY: Widely expressed, with the highest level of expression in the liver and in aorta.

DISEASE: Vitreoretinopathy, exudative 4 (EVR4) OMIM: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. Note=The disease is caused by mutations affecting the gene represented in this entry.

DISEASE: Osteoporosis (OSTEOP) OMIM: A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.

DISEASE: Osteoporosis-pseudoglioma syndrome (OPPG) OMIM: A disease characterized by congenital or infancy-onset blindness and severe juvenile-onset osteoporosis and spontaneous fractures. Additional clinical manifestations may include microphthalmos, abnormalities of the iris, lens or vitreous, cataracts, short stature, microcephaly, ligamental laxity, mental retardation and hypotonia. Note=The disease is caused by mutations affecting the gene represented in this entry.

DISEASE: High bone mass trait (HBM) OMIM: Rare phenotype characterized by exceptionally dense bones. HBM individuals show otherwise a completely normal skeletal structure and no other unusual clinical findings. Note=The disease is caused by mutations affecting the gene represented in this entry.

DISEASE: Endosteal hyperostosis, Worth type (WENHY) OMIM: An autosomal dominant sclerosing bone dysplasia clinically characterized by elongation of the mandible, increased gonial angle, flattened forehead, and the presence of a slowly enlarging osseous prominence of the hard palate (torus palatinus). Serum calcium, phosphorus and alkaline phosphatase levels are normal. Radiologically, it is characterized by early thickening of the endosteum of long bones, the skull and of the mandible. With advancing age, the trabeculae of the metaphysis become thickened. WENHY becomes clinically and radiologically evident by adolescence, does not cause deformity except in the skull and mandible, and is not associated with bone pain or fracture. Affected patients have normal height, proportion, intelligence and longevity. caused by mutations affecting the gene represented in this entry.

DISEASE: Osteopetrosis, autosomal dominant 1 (OPTA1) OMIM: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. OPTA1 is an autosomal dominant form characterized by generalized osteosclerosis most pronounced in the cranial vault. Patients are often asymptomatic, but some suffer from pain and hearing loss. It appears to be the only type of osteopetrosis not associated with an increased fracture rate. caused by mutations affecting the gene represented in this entry.

DISEASE: Van Buchem disease 2 (VBCH2) OMIM: VBCH2 is an autosomal dominant sclerosing bone dysplasia characterized by cranial osteosclerosis, thickened calvaria and cortices of long bones, enlarged mandible and normal serum alkaline phosphatase levels. by mutations affecting the gene represented in this entry.

UniProt features for LRP5_HUMAN » Low-density lipoprotein receptor-related protein 5
SIGNAL 1 31 Potential.
CHAIN 32 1615 Low-density lipoprotein receptor-related protein 5.
REPEAT 75 119 LDL-receptor class B 1.
REPEAT 78 81 YWTD 1.
REPEAT 120 162 LDL-receptor class B 2.
REPEAT 123 126 YWTD 2.
REPEAT 163 206 LDL-receptor class B 3.
REPEAT 166 169 YWTD 3.
REPEAT 207 247 LDL-receptor class B 4.
REPEAT 248 290 LDL-receptor class B 5.
REPEAT 251 254 YWTD 4.
DOMAIN 295 337 EGF-like 1.
REPEAT 385 427 LDL-receptor class B 6.
REPEAT 388 391 YWTD 5.
REPEAT 428 470 LDL-receptor class B 7.
REPEAT 431 434 YWTD 6.
REPEAT 471 514 LDL-receptor class B 8.
REPEAT 474 477 YWTD 7.
REPEAT 515 557 LDL-receptor class B 9.
REPEAT 558 600 LDL-receptor class B 10.
REPEAT 559 562 YWTD 8.
DOMAIN 601 641 EGF-like 2.
REPEAT 687 729 LDL-receptor class B 11.
REPEAT 690 693 YWTD 9.
REPEAT 730 772 LDL-receptor class B 12.
REPEAT 773 815 LDL-receptor class B 13.
REPEAT 816 855 LDL-receptor class B 14.
REPEAT 819 822 YWTD 10.
REPEAT 856 898 LDL-receptor class B 15.
REPEAT 859 862 YWTD 11.
DOMAIN 902 942 EGF-like 3.
REPEAT 989 1035 LDL-receptor class B 16.
REPEAT 1036 1078 LDL-receptor class B 17.
REPEAT 1079 1123 LDL-receptor class B 18.
REPEAT 1124 1164 LDL-receptor class B 19.
REPEAT 1165 1207 LDL-receptor class B 20.
DOMAIN 1213 1254 EGF-like 4.
DOMAIN 1258 1296 LDL-receptor class A 1.
DOMAIN 1297 1333 LDL-receptor class A 2.
DOMAIN 1335 1371 LDL-receptor class A 3.
REGION 32 288 Beta-propeller 1.
REGION 341 602 Beta-propeller 2.
REGION 644 903 Beta-propeller 3.
REGION 945 1212 Beta-propeller 4.
MOTIF 1500 1506 PPPSP motif A.
MOTIF 1538 1545 PPPSP motif B.
MOTIF 1574 1581 PPPSP motif C.
MOTIF 1591 1596 PPPSP motif D.
MOTIF 1605 1612 PPPSP motif E.
DISULFID 299 310 By similarity.
DISULFID 306 321 By similarity.
DISULFID 323 336 By similarity.
DISULFID 605 616 By similarity.
DISULFID 612 625 By similarity.
DISULFID 627 640 By similarity.
DISULFID 906 917 By similarity.
DISULFID 913 926 By similarity.
DISULFID 928 941 By similarity.
DISULFID 1217 1228 By similarity.
DISULFID 1224 1238 By similarity.
DISULFID 1240 1253 By similarity.
DISULFID 1259 1273 By similarity.
DISULFID 1266 1286 By similarity.
DISULFID 1280 1295 By similarity.
DISULFID 1298 1310 By similarity.
DISULFID 1305 1323 By similarity.
DISULFID 1317 1332 By similarity.
DISULFID 1336 1348 By similarity.
DISULFID 1343 1361 By similarity.
DISULFID 1355 1370 By similarity.
Amino Acid Sequence for LRP5_HUMAN » Low-density lipoprotein receptor-related protein 5
MEAAPPGPPW PLLLLLLLLL ALCGCPAPAA ASPLLLFANR RDVRLVDAGG VKLESTIVVS GLEDAAAVDF QFSKGAVYWT DVSEEAIKQT YLNQTGAAVQ NVVISGLVSP DGLACDWVGK KLYWTDSETN RIEVANLNGT SRKVLFWQDL DQPRAIALDP AHGYMYWTDW GETPRIERAG MDGSTRKIIV DSDIYWPNGL TIDLEEQKLY WADAKLSFIH RANLDGSFRQ KVVEGSLTHP FALTLSGDTL YWTDWQTRSI HACNKRTGGK RKEILSALYS PMDIQVLSQE RQPFFHTRCE EDNGGCSHLC LLSPSEPFYT CACPTGVQLQ DNGRTCKAGA EEVLLLARRT DLRRISLDTP DFTDIVLQVD DIRHAIAIDY DPLEGYVYWT DDEVRAIRRA YLDGSGAQTL VNTEINDPDG IAVDWVARNL YWTDTGTDRI EVTRLNGTSR KILVSEDLDE PRAIALHPVM GLMYWTDWGE NPKIECANLD GQERRVLVNA SLGWPNGLAL DLQEGKLYWG DAKTDKIEVI NVDGTKRRTL LEDKLPHIFG FTLLGDFIYW TDWQRRSIER VHKVKASRDV IIDQLPDLMG LKAVNVAKVV GTNPCADRNG GCSHLCFFTP HATRCGCPIG LELLSDMKTC IVPEAFLVFT SRAAIHRISL ETNNNDVAIP LTGVKEASAL DFDVSNNHIY WTDVSLKTIS RAFMNGSSVE HVVEFGLDYP EGMAVDWMGK NLYWADTGTN RIEVARLDGQ FRQVLVWRDL DNPRSLALDP TKGYIYWTEW GGKPRIVRAF MDGTNCMTLV DKVGRANDLT IDYADQRLYW TDLDTNMIES SNMLGQERVV IADDLPHPFG LTQYSDYIYW TDWNLHSIER ADKTSGRNRT LIQGHLDFVM DILVFHSSRQ DGLNDCMHNN GQCGQLCLAI PGGHRCGCAS HYTLDPSSRN CSPPTTFLLF SQKSAISRMI PDDQHSPDLI LPLHGLRNVK AIDYDPLDKF IYWVDGRQNI KRAKDDGTQP FVLTSLSQGQ NPDRQPHDLS IDIYSRTLFW TCEATNTINV HRLSGEAMGV VLRGDRDKPR AIVVNAERGY LYFTNMQDRA AKIERAALDG TEREVLFTTG LIRPVALVVD NTLGKLFWVD ADLKRIESCD LSGANRLTLE DANIVQPLGL TILGKHLYWI DRQQQMIERV EKTTGDKRTR IQGRVAHLTG IHAVEEVSLE EFSAHPCARD NGGCSHICIA KGDGTPRCSC PVHLVLLQNL LTCGEPPTCS PDQFACATGE IDCIPGAWRC DGFPECDDQS DEEGCPVCSA AQFPCARGQC VDLRLRCDGE ADCQDRSDEA DCDAICLPNQ FRCASGQCVL IKQQCDSFPD CIDGSDELMC EITKPPSDDS PAHSSAIGPV IGIILSLFVM GGVYFVCQRV VCQRYAGANG PFPHEYVSGT PHVPLNFIAP GGSQHGPFTG IACGKSMMSS VSLMGGRGGV PLYDRNHVTG ASSSSSSSTK ATLYPPILNP PPSPATDPSL YNMDMFYSSN IPATARPYRP YIIRGMAPPT TPCSTDVCDS DYSASRWKAS KYYLDLNSDS DPYPPPPTPH SQYLSAEDSC PPSPATERSY FHLFPPPPSP CTDSS