| IED ID | IndEnz0005000127 |
| Enzyme Type ID | lipase000127 |
| Protein Name |
Low-density lipoprotein receptor-related protein 2 LRP-2 Glycoprotein 330 gp330 Megalin |
| Gene Name | Lrp2 |
| Organism | Rattus norvegicus (Rat) |
| 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 Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Rattus Rattus norvegicus (Rat) |
| Enzyme Sequence | MERGAAAAAWMLLLAIAACLEPVSSQECGSGNFRCDNGYCIPASWRCDGTRDCLDDTDEIGCPPRSCESGLFLCPAEGTCIPSSWVCDEDKDCSDGADEQQNCAGTTCSAQQMTCSNGQCIPSEYRCDHVSDCPDGSDERNCHYPTCDQLTCANGACYNTSQRCDQKVDCRDSSDEANCTTLCSQKEFECGSGECILRAYVCDHDNDCEDNSDERNCNYDTCGGHQFTCSNGQCINQNWVCDGDDDCQDSGDEDGCESNQSHHRCYPREWACPGSGRCISIDKVCDGVPDCPEGDDENNVTSGRTCGMGVCSVLNCEYQCHQTPFGGECFCPPGHIINSNDSRTCIDFDDCQIWGICDQKCENRQGRHQCLCEEGYILERGQHCKSSDSFSAASVIFSNGRDLLVGDLHGRNFRILAESKNRGMVMGVDFHYQKHRVFWTDPMQEKVFSTDINGLNTQEILNVSVDTPENLAVDWINNKLYLVETKVNRIDVVNLEGNQRVTLITENLGHPRGIALDPTVGYLFFSDWGSLSGQPKVERAFMDGSNRKDLVTTKVGWPAGITLDLVSKRVYWVDSRYDYIETVTYDGIQRKTVARGGSLVPHPFGISLFEEHVFFTDWTKMAVMKASKFTETNPQVYHQSSLRPHGVTVYHALRQPNATNPCGSNNGGCAQVCVLSHRTDNGGLGYRCKCEFGFELDDDEHRCVAVKNFLLFSSKTAVRGIPFTLSTQEDVMVPVTGSPSFFVGIDFDAQHSTVFYSDLSKDIIYKQKIDGTGKEVITANRLESVECLTFDWISRNLYWTDGGLKSVTVLRLADKSRRQIISNLNNPRSIVVHPTAGYMFLSDWFRPAKIMRAWSDGSHLMPIVNTSLGWPNGLAIDWSASRLYWVDAFFDKIEHSTLDGLDRKRLGHVDQMTHPFGLTVFKDNVFITDWRLGAIIRVRKSDGGDMTVIRRGISSVMHVKAYDADLQTGSNYCSQTTHANGDCSHFCFPVPNFQRVCGCPYGMKLQRDQMTCEGDPAREPPTQQCGSLSFPCNNGKCVPSFFRCDGVDDCHDNSDEHQCGVFNNTCSPSAFACVRGGQCIPGQWHCDRQNDCLDGSDEQNCPTHATSSTCPSTSFTCDNHVCIPKDWVCDTDNDCSDGSDEKNCQASGTCQPTQFRCPDHRCISPLYVCDGDKDCADGSDEAGCVLNCTSAQFKCADGSSCINSRYRCDGVYDCRDNSDEAGCPTRPPGMCHPDEFQCQGDGTCIPNTWECDGHPDCIHGSDEHTGCVPKTCSPTHFLCDNGNCIYKAWICDGDNDCRDMSDEKDCPTQPFHCPSTQWQCPGYSTCINLSALCDGVFDCPNGTDESPLCNQDSCSHFNGGCTHQCMQGPFGATCLCPLGYQLANDTKTCEDINECDIPGFCSQHCVNMRGSFRCACDPEYTLESDGRTCKVTGSENPLLVVASRDKIIVDNITAHTHNLYSLVQDVSFVVALDFDSVTGRVFWSDLLQGKTWSVFQNGTDKRVVHDSGLSVTEMIAVDWIGRNLYWTDYALETIEVSKIDGSHRTVLISKNVTKPRGLALDPRMGDNVMFWSDWGHHPRIERASMDGTMRTVIVQEKIYWPCGLSIDYPNRLIYFMDAYLDYIEFCDYDGHNRRQVIASDLVLHHPHALTLFEDFVYWTDRGTRQVMQANKWHGGNQSVVMYSVHQPLGITAIHPSRQPPSRNPCASASCSHLCLLSAQAPRHYSCACPSGWNLSDDSVNCVRGDQPFLMSVRDNIIFGISLDPEVKSNDAMVPISGIQHGYDVEFDDSEQFIYWVENPGEIHRVKTDGSNRTVFAPLSLLGSSLGLALDWVSRNIYYTTPASRSIEVLTLKGDTRYGKTLIANDGTPLGVGFPVGIAVDPARGKLYWSDHGTDSGVPAKIASANMDGTSLKILFTGNLQHLEVVTLDIQEQKLYWAVTSRGVIERGNVDGTERMILVHHLAHPWGLVVYGSFLYYSDEQYEVIERVDKSSGNNKVVLRDNVPYLRGLRVYHRRNAADSSNGCSNNPNACQQICLPVPGGMFSCACASGFKLSPDGRSCSPYNSFMVVSMLPAVRGFSLELSDHSEAMVPVAGQGRNVLHADVDVANGFIYWCDFSSSVRSSNGIRRIKPDGSNFTNVVTYGIGANGIRGVALDWAAGNLYFTNAFVYETLIEVLRINTTYRRVLLKVSVDMPRHIIVDPKHRYLFWADYGQKPKIERSFLDCTNRTVLVSEGIVTPRGLAMDHDTGYIYWVDDSLDLIARIHLDGGESQVVRYGSRYPTPYGITVFGESIIWVDRNLKKVFQASKQPGNTDPPVVIRDKINLLRDVTIFDEHAQPLSPAELNNNPCLQSNGGCSHFCFALPELPTPRCGCAFGTLGNDGKSCATSQEDFLIYSLNNSLRSLHFDPRDHSLPFQVISVAGTAIALDYDRRNNRIFFTQKLNSLRGQISYVSLYSGSSSPTVLLSNIGVTDGIAFDWINRRIYYSDFSNQTINSMAEDGSNRAVIARVSKPRAIVLDPCRGYMYWTDWGTNAKIERATLGGNFRVPIVNTSLVWPNGLALDLETDLLYWADASLQKIERSTLTGTNREVVVSTAFHSFGLTVYGQYIYWTDLYTRKIYRANKYDGSDLVAMTTRLPTQPSGISTVVKTQRQQCSNPCDQFNGGCSHICAPGPNGAECQCPHEGNWYLANDNKYCVVDTGTRCNQLQFTCLNGHCINQDWKCDNDNDCGDGSDELPTVCAFHTCRSTAFTCGNGRCVPYHYRCDYYNDCGDNSDEAGCLFRNCNSTTEFTCSNGRCIPLSYVCNGINNCHDNDTSDEKNCPPHTCPPDFTKCQTTNICVPRAFLCDGDNDCGDGSDENPIYCASHTCRSNEFQCLSPQRCIPSYWFCDGEADCADGSDEPDTCGHSVNTCRASQFQCDNGRCISGNWVCDGDNDCGDMSDEDQRHHCELQNCSSTQFTCVNSRPPNRRCIPQYWVCDGDADCSDALDELQNCTMRTCSAGEFSCANGRCVRQSFRCDRRNDCGDYSDERGCSYPPCHANQFTCQNGRCIPRFFVCDEDNDCGDGSDEQEHLCHTPEPTCPLHQFRCDNGHCIEMGRVCNHVDDCSDNSDEKGCGINECLDSSISRCDHNCTDTITSFYCSCLPGYKLMSDKRSCVDIDECKESPQLCSQKCENVVGSYICKCAPGYIREPDGKSCRQNSNIEPYLIFSNRYYIRNLTTDGSSYSLILQGLGNVVALDFDRVEKRLYWIDAEKQIIERMFLNKTNRETIINHRLRRAESLAVDWVSRKLYWLDAILDCLFVSDLEGRHRKMIAQHCVDANNTFCFEHPRGIVLHPQRGHVYWADWGVHAYIGRIGMDGTNKSVIISTKIEWPNAITIDYTNDLLYWADAHLGYIEFSDLEGHHRHTVYDGSLPHPFALTIFEDTVFWTDWNTRTVEKGNKYDGSGRVVLVNTTHKPFDIHVYHPYRQPIMSNPCGTNNGGCSHLCLIKAGGRGFTCACPDDFQTVQLRDRTLCMPMCSSTQFLCGNNEKCIPIWWKCDGQKDCSDGSDEPDLCPHRFCRLGQFQCRDGNCTSPQALCNARQDCADGSDEDRVLCEHHRCESNEWQCANKRCIPQSWQCDSVNDCLDNSDEDTSHCASRTCRPGQFKCNNGRCIPQSWKCDVDNDCGDYSDEPIDECTTAAYNCDNHTEFSCKTNYRCIPQWAVCNGFDDCRDNSDEQGCESVPCHPSGDFRCANHHCIPLRWKCDGTDDCGDNSDEENCVPRECSESEFRCADQQCIPSRWVCDQENDCGDNSDERDCEMKTCHPEHFQCTSGHCVPKALACDGRADCLDASDESACPTRFPNGTYCPAAMFECKNHVCIQSFWICDGENDCVDGSDEEIHLCFNIPCESPQRFRCDNSRCVYGHQLCNGVDDCGDGSDEKEEHCRKPTHKPCTDTEYKCSNGNCISQHYVCDNVNDCGDLSDETGCNLGDNRTCAENICEQNCTQLSSGGFICSCRPGFKPSTSDKNSCQDINECEEFGICPQSCRNSKGSYECFCVDGFKSMSTHYGERCAADGSPPLLLLPENVRIRKYNTSSEKFSEYLEEEEHIQTIDYDWDPEHIGLSVVYYTVLAQGSQFGAIKRAYIPNFESGSNNPIREVDLGLKYLMQPDGLAVDWVGRHIYWSDAKSQRIEVATLDGRYRKWLITTQLDQPAAIAVNPKLGLMFWTDQGKQPKIESAWMNGEHRSVLVSENLGWPNGLSIDYLNDDRVYWSDSKEDVIEAIKYDGTDRRLIINEAMKPFSLDIFEDKLYWVAKEKGEVWRQNKFGKENKEKVLVVNPWLTQVRIFHQLRYNQSVSNPCKQVCSHLCLLRPGGYSCACPQGSDFVTGSTVQCDAASELPVTMPPPCRCMHGGNCYFDENELPKCKCSSGYSGEYCEVGLSRGIPPGTTMAVLLTFVIVIIVGALVLVGLFHYRKTGSLLPTLPKLPSLSSLAKPSENGNGVTFRSGADVNMDIGVSPFGPETIIDRSMAMNEHFVMEVGKQPVIFENPMYAAKDNTSKVALAVQGPSTGAQVTVPENVENQNYGRPIDPSEIVPEPKPASPGADEIQGKKWNIFKRKPKQTTNFENPIYAEMDSEVKDAVAVAPPPSPSLPAKASKRNLTPGYTATEDTFKDTANLVKEDSDV |
| Enzyme Length | 4660 |
| Uniprot Accession Number | P98158 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: Multiligand endocytic receptor. 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 (PubMed:7544804, PubMed:19202329). 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 (PubMed:17324488). 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 (PubMed:17462596). 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 (PubMed:12724130). Mediates renal uptake and subsequent lysosomal degradation of APOM (PubMed:16099815). 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 (By similarity). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (PubMed:11964399, PubMed:16801528). Also mediates ShhN transcytosis (PubMed:16801528). 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 (PubMed:18466341). 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 (PubMed:16143106). Mediates endocytosis of angiotensin-2 (PubMed:15467006). Also mediates endocytosis of angiotensin 1-7 (PubMed:16380466). 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 (PubMed:17846082). {ECO:0000250|UniProtKB:A2ARV4, ECO:0000250|UniProtKB:C0HL13, ECO:0000250|UniProtKB:P98164, ECO:0000269|PubMed:11964399, ECO:0000269|PubMed:12724130, ECO:0000269|PubMed:15126248, ECO:0000269|PubMed:15467006, ECO:0000269|PubMed:16099815, ECO:0000269|PubMed:16143106, ECO:0000269|PubMed:16380466, ECO:0000269|PubMed:16801528, ECO:0000269|PubMed:17324488, ECO:0000269|PubMed:17462596, ECO:0000269|PubMed:17846082, ECO:0000269|PubMed:18466341, ECO:0000269|PubMed:19202329, ECO:0000269|PubMed:28659595, ECO:0000269|PubMed:7544804}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Beta strand (4); Chain (1); Disulfide bond (130); Domain (44); Glycosylation (42); Helix (2); Metal binding (12); Modified residue (6); Motif (7); Mutagenesis (1); Region (3); Repeat (35); Signal peptide (1); Topological domain (2); Transmembrane (1) |
| Keywords | 3D-structure;Calcium;Cell membrane;Cell projection;Coated pit;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 | O88797; D3ZAR1 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000269|PubMed:12519751, ECO:0000269|PubMed:18466341, ECO:0000269|PubMed:19202329, ECO:0000269|PubMed:6752952}; Single-pass type I membrane protein {ECO:0000255}. Endosome lumen {ECO:0000269|PubMed:17063000}. Membrane, clathrin-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 (PubMed:6752952, PubMed:12724130). In the endolymphatic sac of the inner ear, located in the lumen of endosomes as a soluble form (PubMed:17063000). {ECO:0000269|PubMed:12724130, ECO:0000269|PubMed:6752952}. |
| Modified Residue | MOD_RES 4464; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:22673903; MOD_RES 4467; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:A2ARV4; MOD_RES 4577; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:22673903; MOD_RES 4624; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:22673903; MOD_RES 4637; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:A2ARV4; MOD_RES 4658; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:22673903 |
| 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:0000269|PubMed:23836931}.; PTM: N-glycosylation is required for ligand binding. {ECO:0000250|UniProtKB:A2ARV4}. |
| Signal Peptide | SIGNAL 1..25; /evidence=ECO:0000255 |
| Structure 3D | X-ray crystallography (2); NMR spectroscopy (1) |
| Cross Reference PDB | 2I1P; 3V2O; 3V2X; |
| Mapped Pubmed ID | 10766831; 10769163; 10919857; 11595644; 11685557; 11805171; 11841627; 11880330; 11912251; 12121845; 14528014; 14657389; 15131016; 15266031; 15670845; 16306401; 17453355; 19340093; 21325834; 21372499; 22349218; 26598525; 8626514; 9039057; 9541123; |
| Motif | MOTIF 4454..4463; /note=SH3-binding; /evidence=ECO:0000255; MOTIF 4457..4462; /note=PxLPxI/L motif 1; mediates interaction with ANKRA2; /evidence=ECO:0000269|PubMed:22649097; MOTIF 4460..4465; /note=PxLPxI/L motif 2; mediates interaction with ANKRA2; /evidence=ECO:0000269|PubMed:22649097; MOTIF 4522..4527; /note=Endocytosis signal; /evidence=ECO:0000255; MOTIF 4603..4606; /note=NPXY motif; MOTIF 4606..4609; /note=SH2-binding; /evidence=ECO:0000255; MOTIF 4619..4630; /note=SH3-binding; /evidence=ECO:0000255 |
| Gene Encoded By | |
| Mass | 519,276 |
| Kinetics | |
| Metal Binding | METAL 1127; /note=Calcium; via carbonyl oxygen; /evidence=ECO:0000250|UniProtKB:P98164; METAL 1130; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P98164; METAL 1132; /note=Calcium; via carbonyl oxygen; /evidence=ECO:0000250|UniProtKB:P98164; METAL 1134; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P98164; METAL 1140; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P98164; METAL 1141; /note=Calcium; /evidence=ECO:0000250|UniProtKB:P98164; METAL 1206; /note=Calcium; via carbonyl oxygen; /evidence=ECO:0000269|PubMed:17245526; METAL 1209; /note=Calcium; /evidence=ECO:0000269|PubMed:17245526; METAL 1211; /note=Calcium; via carbonyl oxygen; /evidence=ECO:0000269|PubMed:17245526; METAL 1213; /note=Calcium; /evidence=ECO:0000269|PubMed:17245526; METAL 1219; /note=Calcium; /evidence=ECO:0000269|PubMed:17245526; METAL 1220; /note=Calcium; /evidence=ECO:0000269|PubMed:17245526 |
| Rhea ID | |
| Cross Reference Brenda |