Reviewed,
UniProtKB/Swiss-Prot O75197 (LRP5_HUMAN)
Last modified
November 25, 2008.
Version 75.
History...
Clusters with 100%,
90%,
50% identity |
Documents (5) |
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Names and origin
| Protein names | Recommended name: Low-density lipoprotein receptor-related protein 5 | ||||
| Gene names |
| ||||
| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 1615 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is further processed into a mature form. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Involved in the Wnt/beta catenin signaling pathway, probably by acting as a coreceptor together with Frizzled for Wnt. |
| Subunit structure | Interacts with different Wnt/Frizzled complexes. Interacts with axin. |
| Subcellular location | Membrane; Single-pass type I membrane proteinPotential. |
| Tissue specificity | Widely expressed, with the highest level of expression in the liver. |
| Post-translational modification | Phosphorylation of the PPPSP motif creates an inducible docking site for axin. |
| Polymorphism | Genetic variation in LRP5 contributes to bone-mass and size determination in the general population. |
| Involvement in disease | Defects in LRP5 are the cause of vitreoretinopathy exudative type 4 (EVR4) [MIM:601813]. EVR4 is 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. EVR4 inheritance can be autosomal dominant or recessive. Genetic variations in LRP5 may be associated with susceptibility to involutional osteoporosis [MIM:166710]; also known as senile osteoporosis or postmenopausal osteoporosis. Osteoporosis is characterized by reduced bone mineral density, disrutption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture. Defects in LRP5 are the cause of osteoporosis pseudoglioma syndrome (OPPG) [MIM:259770]. OPPG is a recessive disorder characterized by very low bone mass and blindness. Individualy with OPPG are prone to develop bone fractures and deformations and have various eye abnormalities, including phthisis bulbi, retinal detachments, falciform folds or persistent vitreal vasculature. Defects in LRP5 are a cause of high bone mass trait (HBM) [MIM:601884]. HBM is a rare phenotype characterized by exceptionally dense bones. HBM individuals show otherwise a completely normal skeletal structure and no other unusual clinical findings. Defects in LRP5 are a cause of endosteal hyperostosis Worth type (WENHY) [MIM:144750]; also known as autosomal dominant osteosclerosis. WENHY is an autosomal dominant sclerosing bone dysplasia clinically characterizd 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. Defects in LRP5 are the cause of osteopetrosis autosomal dominant type 1 (OPTA1) [MIM:607634]. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder 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 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. Defects in LRP5 are the cause of van Buchem disease type 2 (VBCH2)[MIM:607636]. 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. |
| Sequence similarities | Belongs to the LDLR family. Contains 4 EGF-like domains. Contains 3 LDL-receptor class A domains. Contains 20 LDL-receptor class B repeats. |
Ontologies
Keywords | |
|---|---|
| Biological process | Endocytosis Wnt signaling pathway |
| Cellular component | Membrane |
| Coding sequence diversity | Polymorphism |
| Disease | Disease mutation Osteopetrosis |
| Domain | EGF-like domain Repeat Signal Transmembrane |
| Molecular function | Developmental protein Receptor |
| PTM | Glycoprotein Phosphoprotein |
Gene Ontology (GO) | |
| Biological process | Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW endocytosisInferred from electronic annotation. Source: UniProtKB-KW lipid metabolic process Ref.1Traceable author statement. Source: ProtInc positive regulation of cell proliferationTraceable author statement. Source: ProtInc |
| Cellular component | integral to membrane Ref.1 Traceable author statement. Source: ProtInc |
| Molecular function | receptor activity Inferred from electronic annotation. Source: UniProtKB-KW |
| Complete GO annotation... | |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||||
Molecule processing | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Signal peptide | 1 – 31 | 31 | Potential | ||||||||
| Chain | 32 – 1615 | 1584 | Low-density lipoprotein receptor-related protein 5 | PRO_0000017328 | |||||||
Regions | |||||||||||
| Topological domain | 32 – 1384 | 1353 | Extracellular Potential | ||||||||
| Transmembrane | 1385 – 1407 | 23 | Potential | ||||||||
| Topological domain | 1408 – 1615 | 208 | Cytoplasmic Potential | ||||||||
| Repeat | 75 – 119 | 45 | LDL-receptor class B 1 | ||||||||
| Repeat | 78 – 81 | 4 | YWTD 1 | ||||||||
| Repeat | 120 – 162 | 43 | LDL-receptor class B 2 | ||||||||
| Repeat | 123 – 126 | 4 | YWTD 2 | ||||||||
| Repeat | 163 – 206 | 44 | LDL-receptor class B 3 | ||||||||
| Repeat | 166 – 169 | 4 | YWTD 3 | ||||||||
| Repeat | 207 – 247 | 41 | LDL-receptor class B 4 | ||||||||
| Repeat | 248 – 290 | 43 | LDL-receptor class B 5 | ||||||||
| Repeat | 251 – 254 | 4 | YWTD 4 | ||||||||
| Domain | 295 – 337 | 43 | EGF-like 1 | ||||||||
| Repeat | 385 – 427 | 43 | LDL-receptor class B 6 | ||||||||
| Repeat | 388 – 391 | 4 | YWTD 5 | ||||||||
| Repeat | 428 – 470 | 43 | LDL-receptor class B 7 | ||||||||
| Repeat | 431 – 434 | 4 | YWTD 6 | ||||||||
| Repeat | 471 – 514 | 44 | LDL-receptor class B 8 | ||||||||
| Repeat | 474 – 477 | 4 | YWTD 7 | ||||||||
| Repeat | 515 – 557 | 43 | LDL-receptor class B 9 | ||||||||
| Repeat | 558 – 600 | 43 | LDL-receptor class B 10 | ||||||||
| Repeat | 559 – 562 | 4 | YWTD 8 | ||||||||
| Domain | 601 – 641 | 41 | EGF-like 2 | ||||||||
| Repeat | 687 – 729 | 43 | LDL-receptor class B 11 | ||||||||
| Repeat | 690 – 693 | 4 | YWTD 9 | ||||||||
| Repeat | 730 – 772 | 43 | LDL-receptor class B 12 | ||||||||
| Repeat | 773 – 815 | 43 | LDL-receptor class B 13 | ||||||||
| Repeat | 816 – 855 | 40 | LDL-receptor class B 14 | ||||||||
| Repeat | 819 – 822 | 4 | YWTD 10 | ||||||||
| Repeat | 856 – 898 | 43 | LDL-receptor class B 15 | ||||||||
| Repeat | 859 – 862 | 4 | YWTD 11 | ||||||||
| Domain | 902 – 942 | 41 | EGF-like 3 | ||||||||
| Repeat | 989 – 1035 | 47 | LDL-receptor class B 16 | ||||||||
| Repeat | 1036 – 1078 | 43 | LDL-receptor class B 17 | ||||||||
| Repeat | 1079 – 1123 | 45 | LDL-receptor class B 18 | ||||||||
| Repeat | 1124 – 1164 | 41 | LDL-receptor class B 19 | ||||||||
| Repeat | 1165 – 1207 | 43 | LDL-receptor class B 20 | ||||||||
| Domain | 1213 – 1254 | 42 | EGF-like 4 | ||||||||
| Domain | 1258 – 1296 | 39 | LDL-receptor class A 1 | ||||||||
| Domain | 1297 – 1333 | 37 | LDL-receptor class A 2 | ||||||||
| Domain | 1335 – 1371 | 37 | LDL-receptor class A 3 | ||||||||
| Motif | 1500 – 1504 | 5 | PPPSP motif | ||||||||
| Motif | 1606 – 1610 | 5 | PPPSP motif | ||||||||
| Compositional bias | 1495 – 1610 | 116 | Pro-rich | ||||||||
Amino acid modifications | |||||||||||
| Glycosylation | 93 | 1 | N-linked (GlcNAc...) Potential | ||||||||
| Glycosylation | 138 | 1 | N-linked (GlcNAc...) Potential | ||||||||
| Glycosylation | 446 | 1 | N-linked (GlcNAc...) Potential | ||||||||
| Glycosylation | 499 | 1 | N-linked (GlcNAc...) Potential | ||||||||
| Glycosylation | 705 | 1 | N-linked (GlcNAc...) Potential | ||||||||
| Glycosylation | 878 | 1 | N-linked (GlcNAc...) Potential | ||||||||
| Disulfide bond | 299 ↔ 310 | By similarity | |||||||||
| Disulfide bond | 306 ↔ 321 | By similarity | |||||||||
| Disulfide bond | 323 ↔ 336 | By similarity | |||||||||
| Disulfide bond | 605 ↔ 616 | By similarity | |||||||||
| Disulfide bond | 612 ↔ 625 | By similarity | |||||||||
| Disulfide bond | 627 ↔ 640 | By similarity | |||||||||
| Disulfide bond | 906 ↔ 917 | By similarity | |||||||||
| Disulfide bond | 913 ↔ 926 | By similarity | |||||||||
| Disulfide bond | 928 ↔ 941 | By similarity | |||||||||
| Disulfide bond | 1217 ↔ 1228 | By similarity | |||||||||
| Disulfide bond | 1224 ↔ 1238 | By similarity | |||||||||
| Disulfide bond | 1240 ↔ 1253 | By similarity | |||||||||
| Disulfide bond | 1259 ↔ 1273 | By similarity | |||||||||
| Disulfide bond | 1266 ↔ 1286 | By similarity | |||||||||
| Disulfide bond | 1280 ↔ 1295 | By similarity | |||||||||
| Disulfide bond | 1298 ↔ 1310 | By similarity | |||||||||
| Disulfide bond | 1305 ↔ 1323 | By similarity | |||||||||
| Disulfide bond | 1317 ↔ 1332 | By similarity | |||||||||
| Disulfide bond | 1336 ↔ 1348 | By similarity | |||||||||
| Disulfide bond | 1343 ↔ 1361 | By similarity | |||||||||
| Disulfide bond | 1355 ↔ 1370 | By similarity | |||||||||
Natural variations | |||||||||||
| Natural variant | 18 – 20 | 3 | Missing | VAR_021804 | |||||||
| Natural variant | 20 | 1 | L → LL | VAR_021805 | |||||||
| Natural variant | 89 | 1 | Q → R: dbSNP rs41494349. | VAR_021806 | |||||||
| Natural variant | 111 | 1 | D → Y in OPTA1. | VAR_021807 | |||||||
| Natural variant | 171 | 1 | G → R in OPTA1. | VAR_021808 | |||||||
| Natural variant | 171 | 1 | G → V in HBM; also in HBM individuals with enlarged mandible and torus palatinus; impairs inhibition of Wnt signaling by Dkk-1. | VAR_021809 | |||||||
| Natural variant | 173 | 1 | T → M in an individual with abnormal retinal vasculature and retinal folds. | VAR_018465 | |||||||
| Natural variant | 214 | 1 | A → T in WENHY. | VAR_021810 | |||||||
| Natural variant | 214 | 1 | A → V in WENHY. | VAR_021811 | |||||||
| Natural variant | 242 | 1 | A → T in OPTA1, VBCH2 and WENHY. | VAR_021812 | |||||||
| Natural variant | 253 | 1 | T → I in OPTA1. | VAR_021813 | |||||||
| Natural variant | 494 | 1 | R → Q in OPPG. | VAR_021814 | |||||||
| Natural variant | 570 | 1 | R → Q in EVR4; autosomal recessive. | VAR_021222 | |||||||
| Natural variant | 570 | 1 | R → W in OPPG. | VAR_021815 | |||||||
| Natural variant | 667 | 1 | V → M: dbSNP rs4988321. | VAR_021816 | |||||||
| Natural variant | 752 | ||||||||||

Clusters with