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0LRP2_HUMAN*   SwissProt (?) | Description Local Annotation Link Reference
General Information
NameLRP2
DescriptionLow-density lipoprotein receptor-related protein 2 precursor (megalin) (glycoprotein 330) (gp330).
SpeciesHomo sapiens (NCBI taxonomy ID: 9606)
GO0005764 lysosome (TAS)
0005515 protein binding (IPI)
0006629 lipid metabolism (TAS)
0006486 protein amino acid glycosylation (TAS)
0006898 receptor mediated endocytosis (TAS)

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schematic display of those terms with internal associations, click the node and browse the corresponding GO term
Domain Architecture (Details)
InterPro domains unassigned to SynO:
Low density lipoprotein (LDL) is the major cholesterol-carrying lipoprotein of plasma. The receptor protein binds LDL and transports it into cells by endocytosis. In order to be internalised.he receptor-ligand complex must first cluster into clathrin-coated pits. Seven successive cysteine-rich repeats of about 40 amino acids are present in the N-terminal of this multidomain membrane protein .The LDL-receptor class A domain contains 6 disulphide-bound cysteines and a highly conserved cluster of negatively charged amino acids.f which many are clustered on one face of the module . A schematic representation of this domain is shown here:In LDL-receptors the class A domains form the binding site for LDL and calcium . The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLRs ligands . The repeat has been shown to consist of a beta-hairpin structure followed by a series of beta turns. In the absence of calcium.DL-A domains are unstructured; the bound calcium ion imparts structural integrity.Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor .Similar domains have been found (see references in ) in several extracellular and membrane proteins (see examples).Numerous familial hypercholestorolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.
  IPR002172:Low density lipoprotein-receptor, class A
A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown .o be present in a large number of membrane-bound and extracellular.ostly animal.roteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N-terminus of some EGF-like domains . Calcium-binding may be crucial for numerous protein-protein interactions.For human coagulation factor IX it has been shown that the calcium-ligands form a pentagonal bipyramid. The first.hird and fourth conserved negatively charged or polar residues are side chain ligands. The latter is possibly hydroxylated (see aspartic acid and asparagine hydroxylation site) . A conserved aromatic residue.s well as the second conserved negative residue.re thought to be involved in stabilizing the calcium-binding site.As in non-calcium binding EGF-like domains.here are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes .
  IPR001881:EGF-like calcium-binding
A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown .o be present in a large number of membrane-bound and extracellular.ostly animal.roteins. Many of these proteins require calcium for their biological function and a calcium-binding site has been found at the N-terminus of some EGF-like domains . Calcium-binding may be crucial for numerous protein-protein interactions.For human coagulation factor IX it has been shown that the calcium-ligands form a pentagonal bipyramid. The first.hird and fourth conserved negatively charged or polar residues are side chain ligands. The latter is possibly hydroxylated (see aspartic acid and asparagine hydroxylation site) . A conserved aromatic residue.s well as the second conserved negative residue.re thought to be involved in stabilizing the calcium-binding site.As in non-calcium binding EGF-like domains.here are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes .
  IPR013091:EGF calcium-binding
The low-density lipoprotein receptor (LDLR) regulates cholesterol homeostasis in mammalian cells. LDLR binds cholesterol-carrying LDL.ssociates with clathrin-coated pits.nd is internalized into acidic endosomes where it separates from its ligand. The ligand is degraded in lysosomes.hile the receptor returns to the cell surface . The LDLR has several domains. The ligand-binding domain contains seven LDL receptor class A repeats.ach with three disulfide bonds and a coordinated Ca2+ ion. The second conserved region contains two EGF repeats.ollowed by six YWTD or LDL receptor class B repeats and another EGF repeat . This conserved region is critical for ligand release and recycling of the receptor . The structure of the six YWTD repeats of LDL receptor have been solved . The six YWTD repeats together fold into a six-bladed beta-propeller. Each blade of the propeller consists of four antiparallel beta-strands; the innermost strand of each blade is labeled 1 and the outermost strand.. The sequence repeats are offset with respect to the blades of the propeller.uch that any given 40-residue YWTD repeat spans strands 24 of one propeller blade and strand 1 of the subsequent blade. This offset ensures circularization of the propeller because the last strand of the final sequence repeat acts as an innermost strand 1 of the blade that harbors strands 24 from the first sequence repeat. The repeat is found in a variety of proteins that include.itellogenin receptor from Drosophila melanogaster.ow-density lipoprotein (LDL) receptor .reproepidermal growth factor.nd nidogen (entactin).
  IPR000033:Low-density lipoprotein receptor, YWTD repeat
A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF)has been shown to be present.n a moreor less conserved form.n a large number of other.ostly animal proteins. The list of proteins currently known tocontain one or more copies of an EGF-like pattern is large and varied. The functional significance of EGF domains inwhat appear to be unrelated proteins is not yet clear. However. common feature is that these repeats are found inthe extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandinG/H synthase). The EGF domain includes six cysteine residues which have been shown (in EGF) to be involved in disulphidebonds. The main structure is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet.Subdomains between the conserved cysteines vary in length.This entry contains EGF domains found in a variety of extracellular and membrane proteins
  IPR013111:EGF, extracellular
A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF)has been shown to be present.n a moreor less conserved form.n a large number of other.ostly animal proteins. The list of proteins currently known tocontain one or more copies of an EGF-like pattern is large and varied. The functional significance of EGF domains inwhat appear to be unrelated proteins is not yet clear. However. common feature is that these repeats are found inthe extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandinG/H synthase). The EGF domain includes six cysteine residues which have been shown (in EGF) to be involved in disulphidebonds. The main structure is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet.Subdomains between the conserved cysteines vary in length.
  IPR006209:EGF-like
The growth factor receptor domain is a cysteine-rich region that is found in a variety of eukaryotic proteins that are involved in the mechanism of signal transduction by receptor tyrosine kinases. Proteins containing the growth factor receptor domain include the insulin-like growth factor-binding proteins (IGFBP) .he type-1 insulin-like growth-factor receptor (IGF-1R) .nd the receptor protein-tyrosine kinase Erbb-3 (ErbB3) . The general structure of the growth factor receptor domain is a disulphide-bound fold containing a beta-hairpin with two adjacent disulphides. IGFBPs control the distribution.unction and activity of insulin-like growth factors (IGFs) IGF-I and IGF-II.hich are key regulators of cell proliferation.ifferentiation and transformation. All IGFBPs share a common domain organization.here the highest conservation is found in the N-terminal Cys-rich IGF-binding domain. The N-terminal domain contains 10-12 conserved cysteine residues. IGF-1R is a member of the tyrosine-kinase receptor superfamily that is involved in both normal growth and development and malignant transformation. The Cys-rich domain is flanked by two L-domains.nd together they contribute to hormone binding and ligand specificity.ven though they do not bind ligand directly. The Cys-rich region is composed of eight disulphide-bonded modules.even of which form a rod-shaped domain. ErbB3 is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. The extracellular region of ErbB3 is made up of two Cys-rich domains and two L-domains.rranged alternately. The two L-domains and the first Cys-rich domain are structurally homologous to those found in IGF-1R. The two Cys-rich domains are extended repeats of seven small disulphide-containing modules. A beta-hairpin loop extends from the first Cys-rich domain to contact the C-terminal portion of the second Cys-rich domain.reating a large pore structure. The SSF signature in this entry is currently under review. Please be aware that some of the protein hits may be false positives.
  IPR009030:Growth factor, receptor
Epidermal growth factors and transforming growth factors belong to a general class of proteins that share a repeat pattern involving a number of conserved Cys residues. Growth factors are involved in cell recognition and division . The repeating pattern.specially of cysteines (the so-called EGF repeat).s thought to be important to the 3D structure of the proteins.nd hence its recognition by receptors and other molecules. The type 1 EGF signature includes six conserved cysteines believed to be involved in disulphide bond formation. The EGF motif is found frequently in nature.articularly in extracellular proteins.
  IPR006210:EGF
IPR002172:Ldl_recept_a 
Evalue:-21.0915145874023 
Location:3633-3671IPR002172:Ldl_recept_a 
Evalue:-19.3467884063721 
Location:2862-2899IPR002172:Ldl_recept_a 
Evalue:-18.6575775146484 
Location:1147-1183IPR002172:Ldl_recept_a 
Evalue:-18.2676067352295 
Location:1065-1101IPR002172:Ldl_recept_a 
Evalue:-18.236572265625 
Location:3717-3754IPR002172:Ldl_recept_a 
Evalue:-18.1870861053467 
Location:2739-2775IPR002172:Ldl_recept_a 
Evalue:-17.236572265625 
Location:1269-1305IPR002172:Ldl_recept_a 
Evalue:-17.1079063415527 
Location:3073-3109IPR002172:Ldl_recept_a 
Evalue:-16.7958793640137 
Location:2991-3027IPR002172:Ldl_recept_a 
Evalue:-16.5376014709473 
Location:3030-3068IPR002172:Ldl_recept_a 
Evalue:-16.3187580108643 
Location:65-103IPR002172:Ldl_recept_a 
Evalue:-16.3010292053223 
Location:3840-3878IPR002172:Ldl_recept_a 
Evalue:-15.8538722991943 
Location:2904-2943IPR002172:LDLa 
Evalue:-15.8239087409443 
Location:3511-3550IPR002172:Ldl_recept_a 
Evalue:-15.795880317688 
Location:3796-3832IPR002172:Ldl_recept_a 
Evalue:-15.6989698410034 
Location:2698-2736IPR002172:Ldl_recept_a 
Evalue:-15.3979396820068 
Location:1024-1060IPR002172:Ldl_recept_a 
Evalue:-15.3872165679932 
Location:181-217IPR002172:Ldl_recept_a 
Evalue:-15.2924299240112 
Location:1107-1143IPR002172:Ldl_recept_a 
Evalue:-15.2076082229614 
Location:220-256IPR002172:Ldl_recept_a 
Evalue:-14.958607673645 
Location:106-142IPR000033:LY 
Evalue:-14.7958800173441 
Location:1544-1589IPR002172:Ldl_recept_a 
Evalue:-14.5228786468506 
Location:3592-3630IPR002172:Ldl_recept_a 
Evalue:-14.3565473556519 
Location:3757-3793IPR002172:Ldl_recept_a 
Evalue:-14.2076082229614 
Location:26-62IPR002172:Ldl_recept_a 
Evalue:-13.6575775146484 
Location:3881-3920IPR002172:Ldl_recept_a 
Evalue:-13.3187589645386 
Location:2946-2988IPR002172:Ldl_recept_a 
Evalue:-12.958607673645 
Location:2820-2859IPR002172:Ldl_recept_a 
Evalue:-12.4685211181641 
Location:3926-3962IPR000033:LY 
Evalue:-12.4685210829577 
Location:1501-1543IPR002172:LDLa 
Evalue:-12.4436974992327 
Location:3677-3716IPR000033:LY 
Evalue:-12.3767507096021 
Location:3357-3399IPR000033:LY 
Evalue:-12.2006594505464 
Location:4221-4264IPR000033:LY 
Evalue:-11.9586073148418 
Location:502-548IPR000033:Ldl_recept_b 
Evalue:-11.6989698410034 
Location:3282-3331IPR013091:EGF_CA 
Evalue:-11.5528421401978 
Location:3152-3191IPR000033:LY 
Evalue:-11.4948500216801 
Location:862-904IPR002172:LDLa 
Evalue:-11.2441251443275 
Location:1186-1224IPR000033:LY 
Evalue:-11.0861861476163 
Location:4177-4220IPR000033:LY 
Evalue:-11 
Location:2182-2225IPR000033:LY 
Evalue:-11 
Location:4134-4176IPR002172:Ldl_recept_a 
Evalue:-10.7447271347046 
Location:1228-1266IPR000033:LY 
Evalue:-10.431798275933 
Location:2543-2585IPR000033:LY 
Evalue:-10.3872161432803 
Location:549-591IPR000033:Ldl_recept_b 
Evalue:-10.3767509460449 
Location:1883-1929IPR000033:LY 
Evalue:-10.1549019599857 
Location:776-818IPR000033:LY 
Evalue:-9.76955107862172 
Location:2226-2268IPR013091:EGF_CA 
Evalue:-9.72124671936035 
Location:4007-4047IPR002172:Ldl_recept_a 
Evalue:-9.63827228546143 
Location:2778-2817IPR001881:EGF_CA 
Evalue:-9.18708664335714 
Location:1390-1429IPR002172:LDLa 
Evalue:-8.95860731484177 
Location:265-303IPR000033:LY 
Evalue:-8.72124639904717 
Location:2458-2500IPR000033:LY 
Evalue:-8.69897000433602 
Location:1590-1632IPR000033:LY 
Evalue:-8.42021640338319 
Location:3219-3261IPR002172:LDLa 
Evalue:-7.60205999132796 
Location:1311-1350IPR000033:LY 
Evalue:-6.88605664769316 
Location:2502-2542IPR002172:LDLa 
Evalue:-6.82390874094432 
Location:3552-3591IPR000033:LY 
Evalue:-6.431798275933 
Location:459-501IPR000033:LY 
Evalue:-5.92081875395237 
Location:3400-3441IPR006209:EGF 
Evalue:-5.74472761154175 
Location:2346-2382IPR000033:LY 
Evalue:-4.74472749489669 
Location:415-458IPR000033:LY 
Evalue:-4.61978875828839 
Location:819-861IPR006210:EGF 
Evalue:-4.52287874528034 
Location:3113-3151IPR000033:Ldl_recept_b 
Evalue:-4.42021656036377 
Location:1931-1971IPR000033:LY 
Evalue:-4.20760831050175 
Location:2135-2181IPR006209:EGF 
Evalue:-3.37675070762634 
Location:1353-1388IPR000033:LY 
Evalue:-3.30102999566398 
Location:1459-1500IPR013111:EGF_2 
Evalue:-2.79588007926941 
Location:4381-4410IPR006210:EGF 
Evalue:-2.56863623584101 
Location:1703-1741IPR006210:EGF 
Evalue:-2.18708664335714 
Location:662-705IPR000033:LY 
Evalue:-1.31875876262441 
Location:1812-1855IPR000033:LY 
Evalue:-1.18708664335714 
Location:1634-1676IPR000033:LY 
Evalue:-1.16749108729376 
Location:733-775IPR000033:LY 
Evalue:-1.11350927482752 
Location:906-947IPR006210:EGF 
Evalue:-1.09151498112135 
Location:3468-3509IPR006210:EGF 
Evalue:-1.0268721464003 
Location:2021-2059IPR006210:EGF 
Evalue:-0.619788758288394 
Location:311-347IPR000033:Ldl_recept_b 
Evalue:-0.60206001996994 
Location:1972-2012IPR000033:LY 
Evalue:-0.508638306165727 
Location:2586-2626IPR000033:Ldl_recept_b 
Evalue:-0.0705810710787773 
Location:613-653IPR006210:EGF 
Evalue:-0.0222763947111522 
Location:3969-4006IPR002172:LDLRA_2 
Evalue:0 
Location:146-180IPR013032:EGF_2 
Evalue:0 
Location:371-385IPR000977:DNA_LIGASE_A1 
Evalue:0 
Location:0-0IPR000033:Ldl_recept_b 
Evalue:0.204119980335236 
Location:2290-2331IPR006210:EGF 
Evalue:0.278753600952829 
Location:973-1014IPR000033:LY 
Evalue:0.826074802700826 
Location:2087-2134IPR006210:EGF 
Evalue:1 
Location:4333-4365IPR000033:LY 
Evalue:1.20411998265592 
Location:1770-1811IPR006210:EGF 
Evalue:1.38021124171161 
Location:2654-2693IPR000033:LY 
Evalue:1.7481880270062 
Location:4265-4304IPR000033:LY 
Evalue:1.99122607569249 
Location:2413-2453
SequencesProtein: LRP2_HUMAN (4655 aa)
mRNA: NM_004525
Local Annotation
Synapse Ontology
endocytosis may be initiated or blocked by all kinds of signal.
sdb:0257 regulation of endocytosis  (Evidence:keywords)
Calcium release from RyR (Ryanodine Receptor) in the SR (Sarcoplasmic Reticulum) is activated by the calcium induced-calcium-release
sdb:0325 RyR-CICR  (Evidence:keywords)
KO assignmentK06233
  Level 3 annotation:
    low density lipoprotein-related protein 2
  Level 2 annotation:
    Hedgehog signaling pathway
Loci Structure (Details)Loci index, Chromosomal location, Length, Possible relational loci clusterExon1: 161 residues, 169693106-169693586Exon2: 26 residues, 169693768-169693840Exon3: 38 residues, 169697329-169697437Exon4: 36 residues, 169702147-169702249Exon5: 45 residues, 169703332-169703462Exon6: 42 residues, 169704006-169704127Exon7: 24 residues, 169704298-169704366Exon8: 32 residues, 169705210-169705301Exon9: 42 residues, 169707429-169707549Exon10: 61 residues, 169710502-169710679Exon11: 75 residues, 169711494-169711715Exon12: 45 residues, 169715653-169715782Exon13: 57 residues, 169717554-169717720Exon14: 50 residues, 169719215-169719359Exon15: 46 residues, 169721029-169721161Exon16: 46 residues, 169722126-169722258Exon17: 45 residues, 169727227-169727356Exon18: 43 residues, 169730687-169730810Exon19: 48 residues, 169733294-169733432Exon20: 41 residues, 169734457-169734574Exon21: 41 residues, 169735306-169735423Exon22: 42 residues, 169736770-169736890Exon23: 45 residues, 169737851-169737980Exon24: 84 residues, 169738674-169738920Exon25: 67 residues, 169739948-169740145Exon26: 61 residues, 169741166-169741344Exon27: 76 residues, 169742558-169742782Exon28: 59 residues, 169746203-169746374Exon29: 53 residues, 169746922-169747075Exon30: 174 residues, 169750258-169750775Exon31: 100 residues, 169752725-169753021Exon32: 69 residues, 169756587-169756789Exon33: 46 residues, 169758516-169758648Exon34: 42 residues, 169761666-169761786Exon35: 44 residues, 169763541-169763667Exon36: 83 residues, 169766383-169766626Exon37: 70 residues, 169767511-169767715Exon38: 98 residues, 169768737-169769027Exon39: 55 residues, 169770234-169770393Exon40: 57 residues, 169770778-169770944Exon41: 309 residues, 169771085-169772006Exon42: 65 residues, 169774208-169774397Exon43: 82 residues, 169776723-169776963Exon44: 73 residues, 169778412-169778626Exon45: 61 residues, 169781008-169781186Exon46: 38 residues, 169785209-169785319Exon47: 50 residues, 169790065-169790209Exon48: 57 residues, 169791177-169791344Exon49: 45 residues, 169796469-169796598Exon50: 61 residues, 169798166-169798344Exon51: 78 residues, 169800595-169800824Exon52: 63 residues, 169801858-169802043Exon53: 72 residues, 169802846-169803058Exon54: 85 residues, 169804282-169804531Exon55: 128 residues, 169805743-169806121Exon56: 41 residues, 169807711-169807828Exon57: 42 residues, 169808158-169808278Exon58: 82 residues, 169809448-169809688Exon59: 96 residues, 169811460-169811742Exon60: 48 residues, 169812133-169812271Exon61: 45 residues, 169820861-169820992Exon62: 44 residues, 169821879-169822005Exon63: 66 residues, 169823780-169823973Exon64: 70 residues, 169835659-169835863Exon65: 49 residues, 169837682-169837823Exon66: 69 residues, 169839791-169839994Exon67: 71 residues, 169842500-169842707Exon68: 76 residues, 169844127-169844351Exon69: 58 residues, 169845105-169845275Exon70: 45 residues, 169847628-169847757Exon71: 42 residues, 169853781-169853901Exon72: 53 residues, 169855600-169855753Exon73: 41 residues, 169857008-169857125Exon74: 40 residues, 169858903-169859017Exon75: 39 residues, 169859355-169859466Exon76: 41 residues, 169872036-169872153Exon77: 43 residues, 169883517-169883640Exon78: 38 residues, 169885532-169885640Exon79: 63 residues, 169927076-169927259Exon80: 2 residues, -Jump to LRP2_HUMAN  
Tune and view alternative isoforms
Loci Cluster (Details)Loci: 4477 169693106-169927259 ~-234K 21526(LRP2)(-)Loci: 4476 169435647-169455190 ~-20K 21519(-)Link out to UCSC