| IED ID | IndEnz0005000124 |
| Enzyme Type ID | lipase000124 |
| Protein Name |
Low-density lipoprotein receptor-related protein 2 LRP-2 Glycoprotein 330 gp330 Megalin |
| Gene Name | LRP2 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MDRGPAAVACTLLLALVACLAPASGQECDSAHFRCGSGHCIPADWRCDGTKDCSDDADEIGCAVVTCQQGYFKCQSEGQCIPNSWVCDQDQDCDDGSDERQDCSQSTCSSHQITCSNGQCIPSEYRCDHVRDCPDGADENDCQYPTCEQLTCDNGACYNTSQKCDWKVDCRDSSDEINCTEICLHNEFSCGNGECIPRAYVCDHDNDCQDGSDEHACNYPTCGGYQFTCPSGRCIYQNWVCDGEDDCKDNGDEDGCESGPHDVHKCSPREWSCPESGRCISIYKVCDGILDCPGREDENNTSTGKYCSMTLCSALNCQYQCHETPYGGACFCPPGYIINHNDSRTCVEFDDCQIWGICDQKCESRPGRHLCHCEEGYILERGQYCKANDSFGEASIIFSNGRDLLIGDIHGRSFRILVESQNRGVAVGVAFHYHLQRVFWTDTVQNKVFSVDINGLNIQEVLNVSVETPENLAVDWVNNKIYLVETKVNRIDMVNLDGSYRVTLITENLGHPRGIAVDPTVGYLFFSDWESLSGEPKLERAFMDGSNRKDLVKTKLGWPAGVTLDMISKRVYWVDSRFDYIETVTYDGIQRKTVVHGGSLIPHPFGVSLFEGQVFFTDWTKMAVLKANKFTETNPQVYYQASLRPYGVTVYHSLRQPYATNPCKDNNGGCEQVCVLSHRTDNDGLGFRCKCTFGFQLDTDERHCIAVQNFLIFSSQVAIRGIPFTLSTQEDVMVPVSGNPSFFVGIDFDAQDSTIFFSDMSKHMIFKQKIDGTGREILAANRVENVESLAFDWISKNLYWTDSHYKSISVMRLADKTRRTVVQYLNNPRSVVVHPFAGYLFFTDWFRPAKIMRAWSDGSHLLPVINTTLGWPNGLAIDWAASRLYWVDAYFDKIEHSTFDGLDRRRLGHIEQMTHPFGLAIFGEHLFFTDWRLGAIIRVRKADGGEMTVIRSGIAYILHLKSYDVNIQTGSNACNQPTHPNGDCSHFCFPVPNFQRVCGCPYGMRLASNHLTCEGDPTNEPPTEQCGLFSFPCKNGRCVPNYYLCDGVDDCHDNSDEQLCGTLNNTCSSSAFTCGHGECIPAHWRCDKRNDCVDGSDEHNCPTHAPASCLDTQYTCDNHQCISKNWVCDTDNDCGDGSDEKNCNSTETCQPSQFNCPNHRCIDLSFVCDGDKDCVDGSDEVGCVLNCTASQFKCASGDKCIGVTNRCDGVFDCSDNSDEAGCPTRPPGMCHSDEFQCQEDGICIPNFWECDGHPDCLYGSDEHNACVPKTCPSSYFHCDNGNCIHRAWLCDRDNDCGDMSDEKDCPTQPFRCPSWQWQCLGHNICVNLSVVCDGIFDCPNGTDESPLCNGNSCSDFNGGCTHECVQEPFGAKCLCPLGFLLANDSKTCEDIDECDILGSCSQHCYNMRGSFRCSCDTGYMLESDGRTCKVTASESLLLLVASQNKIIADSVTSQVHNIYSLVENGSYIVAVDFDSISGRIFWSDATQGKTWSAFQNGTDRRVVFDSSIILTETIAIDWVGRNLYWTDYALETIEVSKIDGSHRTVLISKNLTNPRGLALDPRMNEHLLFWSDWGHHPRIERASMDGSMRTVIVQDKIFWPCGLTIDYPNRLLYFMDSYLDYMDFCDYNGHHRRQVIASDLIIRHPYALTLFEDSVYWTDRATRRVMRANKWHGGNQSVVMYNIQWPLGIVAVHPSKQPNSVNPCAFSRCSHLCLLSSQGPHFYSCVCPSGWSLSPDLLNCLRDDQPFLITVRQHIIFGISLNPEVKSNDAMVPIAGIQNGLDVEFDDAEQYIYWVENPGEIHRVKTDGTNRTVFASISMVGPSMNLALDWISRNLYSTNPRTQSIEVLTLHGDIRYRKTLIANDGTALGVGFPIGITVDPARGKLYWSDQGTDSGVPAKIASANMDGTSVKTLFTGNLEHLECVTLDIEEQKLYWAVTGRGVIERGNVDGTDRMILVHQLSHPWGIAVHDSFLYYTDEQYEVIERVDKATGANKIVLRDNVPNLRGLQVYHRRNAAESSNGCSNNMNACQQICLPVPGGLFSCACATGFKLNPDNRSCSPYNSFIVVSMLSAIRGFSLELSDHSETMVPVAGQGRNALHVDVDVSSGFIYWCDFSSSVASDNAIRRIKPDGSSLMNIVTHGIGENGVRGIAVDWVAGNLYFTNAFVSETLIEVLRINTTYRRVLLKVTVDMPRHIVVDPKNRYLFWADYGQRPKIERSFLDCTNRTVLVSEGIVTPRGLAVDRSDGYVYWVDDSLDIIARIRINGENSEVIRYGSRYPTPYGITVFENSIIWVDRNLKKIFQASKEPENTEPPTVIRDNINWLRDVTIFDKQVQPRSPAEVNNNPCLENNGGCSHLCFALPGLHTPKCDCAFGTLQSDGKNCAISTENFLIFALSNSLRSLHLDPENHSPPFQTINVERTVMSLDYDSVSDRIYFTQNLASGVGQISYATLSSGIHTPTVIASGIGTADGIAFDWITRRIYYSDYLNQMINSMAEDGSNRTVIARVPKPRAIVLDPCQGYLYWADWDTHAKIERATLGGNFRVPIVNSSLVMPSGLTLDYEEDLLYWVDASLQRIERSTLTGVDREVIVNAAVHAFGLTLYGQYIYWTDLYTQRIYRANKYDGSGQIAMTTNLLSQPRGINTVVKNQKQQCNNPCEQFNGGCSHICAPGPNGAECQCPHEGNWYLANNRKHCIVDNGERCGASSFTCSNGRCISEEWKCDNDNDCGDGSDEMESVCALHTCSPTAFTCANGRCVQYSYRCDYYNDCGDGSDEAGCLFRDCNATTEFMCNNRRCIPREFICNGVDNCHDNNTSDEKNCPDRTCQSGYTKCHNSNICIPRVYLCDGDNDCGDNSDENPTYCTTHTCSSSEFQCASGRCIPQHWYCDQETDCFDASDEPASCGHSERTCLADEFKCDGGRCIPSEWICDGDNDCGDMSDEDKRHQCQNQNCSDSEFLCVNDRPPDRRCIPQSWVCDGDVDCTDGYDENQNCTRRTCSENEFTCGYGLCIPKIFRCDRHNDCGDYSDERGCLYQTCQQNQFTCQNGRCISKTFVCDEDNDCGDGSDELMHLCHTPEPTCPPHEFKCDNGRCIEMMKLCNHLDDCLDNSDEKGCGINECHDPSISGCDHNCTDTLTSFYCSCRPGYKLMSDKRTCVDIDECTEMPFVCSQKCENVIGSYICKCAPGYLREPDGKTCRQNSNIEPYLIFSNRYYLRNLTIDGYFYSLILEGLDNVVALDFDRVEKRLYWIDTQRQVIERMFLNKTNKETIINHRLPAAESLAVDWVSRKLYWLDARLDGLFVSDLNGGHRRMLAQHCVDANNTFCFDNPRGLALHPQYGYLYWADWGHRAYIGRVGMDGTNKSVIISTKLEWPNGITIDYTNDLLYWADAHLGYIEYSDLEGHHRHTVYDGALPHPFAITIFEDTIYWTDWNTRTVEKGNKYDGSNRQTLVNTTHRPFDIHVYHPYRQPIVSNPCGTNNGGCSHLCLIKPGGKGFTCECPDDFRTLQLSGSTYCMPMCSSTQFLCANNEKCIPIWWKCDGQKDCSDGSDELALCPQRFCRLGQFQCSDGNCTSPQTLCNAHQNCPDGSDEDRLLCENHHCDSNEWQCANKRCIPESWQCDTFNDCEDNSDEDSSHCASRTCRPGQFRCANGRCIPQAWKCDVDNDCGDHSDEPIEECMSSAHLCDNFTEFSCKTNYRCIPKWAVCNGVDDCRDNSDEQGCEERTCHPVGDFRCKNHHCIPLRWQCDGQNDCGDNSDEENCAPRECTESEFRCVNQQCIPSRWICDHYNDCGDNSDERDCEMRTCHPEYFQCTSGHCVHSELKCDGSADCLDASDEADCPTRFPDGAYCQATMFECKNHVCIPPYWKCDGDDDCGDGSDEELHLCLDVPCNSPNRFRCDNNRCIYSHEVCNGVDDCGDGTDETEEHCRKPTPKPCTEYEYKCGNGHCIPHDNVCDDADDCGDWSDELGCNKGKERTCAENICEQNCTQLNEGGFICSCTAGFETNVFDRTSCLDINECEQFGTCPQHCRNTKGSYECVCADGFTSMSDRPGKRCAAEGSSPLLLLPDNVRIRKYNLSSERFSEYLQDEEYIQAVDYDWDPKDIGLSVVYYTVRGEGSRFGAIKRAYIPNFESGRNNLVQEVDLKLKYVMQPDGIAVDWVGRHIYWSDVKNKRIEVAKLDGRYRKWLISTDLDQPAAIAVNPKLGLMFWTDWGKEPKIESAWMNGEDRNILVFEDLGWPTGLSIDYLNNDRIYWSDFKEDVIETIKYDGTDRRVIAKEAMNPYSLDIFEDQLYWISKEKGEVWKQNKFGQGKKEKTLVVNPWLTQVRIFHQLRYNKSVPNLCKQICSHLCLLRPGGYSCACPQGSSFIEGSTTECDAAIELPINLPPPCRCMHGGNCYFDETDLPKCKCPSGYTGKYCEMAFSKGISPGTTAVAVLLTILLIVVIGALAIAGFFHYRRTGSLLPALPKLPSLSSLVKPSENGNGVTFRSGADLNMDIGVSGFGPETAIDRSMAMSEDFVMEMGKQPIIFENPMYSARDSAVKVVQPIQVTVSENVDNKNYGSPINPSEIVPETNPTSPAADGTQVTKWNLFKRKSKQTTNFENPIYAQMENEQKESVAATPPPSPSLPAKPKPPSRRDPTPTYSATEDTFKDTANLVKEDSEV |
| Enzyme Length | 4655 |
| Uniprot Accession Number | P98164 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: Multiligand endocytic receptor (By similarity). Acts together with CUBN to mediate endocytosis of high-density lipoproteins (By similarity). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (By similarity). In the kidney, mediates the tubular uptake and clearance of leptin (By similarity). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (By similarity). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (By similarity). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (By similarity). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (By similarity). Mediates renal uptake of metallothionein-bound heavy metals (PubMed:15126248). Together with CUBN, mediates renal reabsorption of myoglobin (By similarity). Mediates renal uptake and subsequent lysosomal degradation of APOM (By similarity). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (By similarity). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (PubMed:23825075). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (By similarity). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (By similarity). Also mediates ShhN transcytosis (By similarity). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (By similarity). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (By similarity). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (By similarity). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (By similarity). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (By similarity). Involved in neurite branching (By similarity). During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells (By similarity). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (By similarity). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (By similarity). Mediates endocytosis of angiotensin-2 (By similarity). Also mediates endocytosis of angiotensis 1-7 (By similarity). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (By similarity). Required for normal hearing, possibly through interaction with estrogen in the inner ear (By similarity). {ECO:0000250|UniProtKB:A2ARV4, ECO:0000250|UniProtKB:C0HL13, ECO:0000250|UniProtKB:P98158, ECO:0000269|PubMed:15126248, ECO:0000269|PubMed:23825075}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Beta strand (4); Chain (1); Compositional bias (1); Disulfide bond (126); Domain (42); Glycosylation (40); Helix (1); Metal binding (11); Modified residue (6); Motif (7); Natural variant (20); Region (3); Repeat (35); Sequence conflict (16); Signal peptide (1); Topological domain (2); Transmembrane (1) |
| Keywords | 3D-structure;Calcium;Cell membrane;Cell projection;Coated pit;Disease variant;Disulfide bond;EGF-like domain;Endocytosis;Endosome;Glycoprotein;Hearing;Membrane;Metal-binding;Neurogenesis;Phosphoprotein;Receptor;Reference proteome;Repeat;SH3-binding;Signal;Transmembrane;Transmembrane helix;Transport |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000269|PubMed:23825075, ECO:0000269|PubMed:27798286}; Single-pass type I membrane protein {ECO:0000255}. Endosome lumen {ECO:0000250|UniProtKB:P98158}. Membrane, coated pit {ECO:0000250|UniProtKB:A2ARV4}. Cell projection, dendrite {ECO:0000250|UniProtKB:A2ARV4}. Cell projection, axon {ECO:0000250|UniProtKB:A2ARV4}. Note=Localizes to brush border membranes in the kidney. In the endolymphatic sac of the inner ear, located in the lumen of endosomes as a soluble form. {ECO:0000250|UniProtKB:P98158}. |
| Modified Residue | MOD_RES 4463; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:A2ARV4; MOD_RES 4466; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:A2ARV4; MOD_RES 4569; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:A2ARV4; MOD_RES 4616; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:P98158; MOD_RES 4632; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:A2ARV4; MOD_RES 4653; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:A2ARV4 |
| Post Translational Modification | PTM: A fraction undergoes proteolytic cleavage of the extracellular domain at the cell membrane to generate a cytoplasmic tail fragment. This is internalized into the early endosome from where it trafficks in an LDLRAP1/ARH-dependent manner to the endocytic recycling compartment (ERC). In the ERC, it is further cleaved by gamma-secretase to release a fragment which translocates to the nucleus and mediates transcriptional repression. {ECO:0000250|UniProtKB:P98158}.; PTM: N-glycosylation is required for ligand binding. {ECO:0000250|UniProtKB:A2ARV4}. |
| Signal Peptide | SIGNAL 1..25; /evidence=ECO:0000255 |
| Structure 3D | NMR spectroscopy (1) |
| Cross Reference PDB | 2M0P; |
| Mapped Pubmed ID | 10052453; 10535736; 10542231; 10559861; 10559924; 10625686; 10766823; 11082044; 11231140; 11239472; 11470803; 11517213; 11532990; 11577110; 11889126; 11927540; 11994745; 12057195; 12234931; 12723989; 12768436; 12952949; 14622578; 14622579; 14657389; 15252009; 15260957; 15318165; 15502812; 15502813; 15649145; 15670845; 15703209; 15895077; 16103228; 16174284; 16215232; 16326391; 16410077; 16516836; 16713569; 16798879; 16828734; 16903783; 17018281; 17158794; 17457342; 17474147; 17512409; 17540576; 17555532; 17609109; 17681954; 17765681; 17978091; 17979745; 18070591; 18093523; 18174661; 18388313; 18448595; 18559602; 18685438; 18790740; 18791690; 18981233; 19092055; 19296720; 19458185; 19536138; 19575674; 19603039; 19696796; 19913121; 19940034; 20031551; 20033059; 20038220; 20052685; 20059951; 20195357; 20231386; 20379614; 20428113; 20448150; 20468071; 20628086; 20826345; 20946875; 20971101; 21104416; 2115402; 21187331; 21278753; 21316588; 21445324; 21482805; 21595846; 21613550; 21779028; 21841790; 21888893; 21927000; 21927001; 21962517; 21971085; 22099461; 22170372; 22174918; 22233676; 22437417; 22505844; 22565184; 22578327; 23274376; 23297414; 23536704; 23673647; 23823722; 23861397; 23891661; 23909735; 23978537; 24093454; 24186068; 24197071; 24254699; 24286387; 24366390; 24581490; 24789820; 24876117; 24966051; 25107275; 25304941; 25341920; 25502002; 25585665; 26042225; 26147675; 26439398; 26638075; 26872844; 27072056; 27197912; 27241555; 27766457; 28138564; 28289043; 28331063; 28356267; 28446629; 28739605; 29090957; 29187367; 29303040; 29388841; 29728895; 29916093; 30355654; 31602990; 31707037; 31821692; 31975031; 32448110; 32803705; 33006316; 33084977; 33103447; 34872573; 6146630; 7683668; 7877694; 8524399; 8552632; 9092476; 9100026; 9427626; 9428629; 9635431; 9736607; |
| Motif | MOTIF 4453..4462; /note=SH3-binding; /evidence=ECO:0000255; MOTIF 4456..4461; /note=PxLPxI/L motif 1; mediates interaction with ANKRA2; /evidence=ECO:0000250|UniProtKB:P98158; MOTIF 4459..4464; /note=PxLPxI/L motif 2; mediates interaction with ANKRA2; /evidence=ECO:0000250|UniProtKB:P98158; MOTIF 4521..4526; /note=Endocytosis signal; /evidence=ECO:0000255; MOTIF 4595..4598; /note=NPXY motif; MOTIF 4598..4601; /note=SH2-binding; /evidence=ECO:0000255; MOTIF 4611..4622; /note=SH3-binding; /evidence=ECO:0000255 |
| Gene Encoded By | |
| Mass | 521,958 |
| Kinetics | |
| Metal Binding | METAL 1126; /note="Calcium; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:23275343, ECO:0007744|PDB:2M0P"; METAL 1129; /note="Calcium"; /evidence="ECO:0000269|PubMed:23275343, ECO:0007744|PDB:2M0P"; METAL 1131; /note="Calcium; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:23275343, ECO:0007744|PDB:2M0P"; METAL 1133; /note="Calcium"; /evidence="ECO:0000269|PubMed:23275343, ECO:0007744|PDB:2M0P"; METAL 1139; /note="Calcium"; /evidence="ECO:0000269|PubMed:23275343, ECO:0007744|PDB:2M0P"; METAL 1140; /note="Calcium"; /evidence="ECO:0000269|PubMed:23275343, ECO:0007744|PDB:2M0P"; METAL 1208; /note="Calcium"; /evidence="ECO:0000250|UniProtKB:P98158"; METAL 1210; /note="Calcium; via carbonyl oxygen"; /evidence="ECO:0000250|UniProtKB:P98158"; METAL 1212; /note="Calcium"; /evidence="ECO:0000250|UniProtKB:P98158"; METAL 1218; /note="Calcium"; /evidence="ECO:0000250|UniProtKB:P98158"; METAL 1219; /note="Calcium"; /evidence="ECO:0000250|UniProtKB:P98158" |
| Rhea ID | |
| Cross Reference Brenda |