ldl receptor related protein associated protein


Summary: A membrane protein found in the rough endoplasm reticulum (ENDOPLASMIC RETICULUM, ROUGH) that binds to LDL-RECEPTOR RELATED PROTEINS. It may function to prevent ligand binding of receptors during protein processing events within endosomal compartments.

Top Publications

  1. Jacobsen L, Madsen P, Moestrup S, Lund A, Tommerup N, Nykjaer A, et al. Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein. J Biol Chem. 1996;271:31379-83 pubmed
    ..The domain structure suggests that sorLA-1 is an endocytic receptor possibly implicated in the uptake of lipoproteins and of proteases. ..
  2. Lazic A, Dolmer K, Strickland D, Gettins P. Structural organization of the receptor associated protein. Biochemistry. 2003;42:14913-20 pubmed
    ..Whereas domains 1D and 2D do not interact with one another, 3D interacts with 2D, both in a 2D-3D construct and in intact RAP. Sedimentation measurements also indicated that intact RAP, although monomeric, is significantly elongated. ..
  3. Orlando R. The low-density lipoprotein receptor-related protein associates with calnexin, calreticulin, and protein disulfide isomerase in receptor-associated-protein-deficient fibroblasts. Exp Cell Res. 2004;294:244-53 pubmed
    ..In RAP -/- cells, three well-known ER chaperones, calnexin, calreticulin, and protein disulfide isomerase (PDI), associate with LRP and likely compensate for the absence of RAP. ..
  4. Van Uden E, Mallory M, Veinbergs I, Alford M, Rockenstein E, Masliah E. Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein. J Neurosci. 2002;22:9298-304 pubmed
    ..Together, these results further support the contention that LRP and other lipoprotein receptors might be neuroprotective against Abeta toxicity and that this receptor might play an integral role in Abeta clearance. ..
  5. Andersen O, Schwarz F, Eisenstein E, Jacobsen C, Moestrup S, Etzerodt M, et al. Dominant thermodynamic role of the third independent receptor binding site in the receptor-associated protein RAP. Biochemistry. 2001;40:15408-17 pubmed
  6. Estrada K, Fisher C, Blacklow S. Unfolding of the RAP-D3 helical bundle facilitates dissociation of RAP-receptor complexes. Biochemistry. 2008;47:1532-9 pubmed publisher
    ..Our studies support a model in which low pH-dependent unfolding of RAP-D3 facilitates dissociation of RAP from the LA repeats of LDLR family proteins in the mildly acidic pH of the Golgi. ..
  7. Bu G, Rennke S. Receptor-associated protein is a folding chaperone for low density lipoprotein receptor-related protein. J Biol Chem. 1996;271:22218-24 pubmed
    ..Thus, our results strongly suggest that, in addition to the prevention of premature binding of ligands to LRP, RAP also plays an important role in receptor folding. ..
  8. Lee D, Walsh J, Migliorini M, Yu P, Cai T, Schwieters C, et al. The structure of receptor-associated protein (RAP). Protein Sci. 2007;16:1628-40 pubmed
    ..The flexible linkers and the quasi-repetitive structural architecture may allow RAP to adopt various possible conformations when interacting with the LDL receptors, which are also made of repetitive substructure units. ..
  9. Deane R, Wu Z, Zlokovic B. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke. 2004;35:2628-31 pubmed

More Information


  1. Bu G, Rennke S, Geuze H. ERD2 proteins mediate ER retention of the HNEL signal of LRP's receptor-associated protein (RAP). J Cell Sci. 1997;110 ( Pt 1):65-73 pubmed
    ..Taken together, our results thus demonstrate that ERD2 proteins are capable of retaining the novel ER retention signal associated with RAP. ..
  2. Willnow T, Armstrong S, Hammer R, Herz J. Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc Natl Acad Sci U S A. 1995;92:4537-41 pubmed
    ..These results are consistent with the hypothesis that RAP stabilizes LRP within the secretory pathway. They also suggest a further mechanism by which the activity of an endocytic receptor may be modulated in vivo. ..
  3. Orlando R, Farquhar M. Functional domains of the receptor-associated protein (RAP). Proc Natl Acad Sci U S A. 1994;91:3161-5 pubmed
    ..These data demonstrate that the gp330 and heparin binding sites and the Heymann nephritis pathogenic epitope (amino acids 1-86) demonstrated earlier are represented by distinct domains of the RAP polypeptide. ..
  4. Bu G, Geuze H, Strous G, Schwartz A. 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein. EMBO J. 1995;14:2269-80 pubmed
    ..Taken together, our results thus suggest that RAP functions intracellularly as a molecular chaperone for LRP and regulates its ligand binding activity along the secretory pathway. ..
  5. Fisher C, Beglova N, Blacklow S. Structure of an LDLR-RAP complex reveals a general mode for ligand recognition by lipoprotein receptors. Mol Cell. 2006;22:277-83 pubmed
  6. Lindner I, Hemdan N, Buchold M, Huse K, Bigl M, Oerlecke I, et al. Alpha2-macroglobulin inhibits the malignant properties of astrocytoma cells by impeding beta-catenin signaling. Cancer Res. 2010;70:277-87 pubmed publisher
    ..Notably, LRP1 antibodies could phenocopy the effects of A2M*. Our findings suggest a pathway of tumor suppression in astrocytoma that might be tractable to therapeutic exploitation...
  7. Irizarry M, Deng A, Lleo A, Berezovska O, von Arnim C, Martin Rehrmann M, et al. Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein. J Neurochem. 2004;90:1132-43 pubmed
    ..The apoE modulation of Abeta production and APP signaling is a potential mechanism affecting Alzheimer disease risk. ..
  8. Page S, Judson A, Melford K, Bensadoun A. Interaction of lipoprotein lipase and receptor-associated protein. J Biol Chem. 2006;281:13931-8 pubmed
    ..A function of RAP may be to prevent premature interaction of LPL with binding partners in the secretory pathway, namely LRP and heparan sulfate proteoglycan. ..
  9. Coukos G, Gafvels M, Wisel S, Ruelaz E, Strickland D, Strauss J, et al. Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and the 39-kd receptor-associated protein in human trophoblasts. Am J Pathol. 1994;144:383-92 pubmed
    ..The patterns of alpha 2MR/LRP and RAP expression in trophoblast cells are consistent with roles for the receptor in trophoblast invasion and transport of molecules across the syncytiotrophoblast. ..
  10. Taira K, Bujo H, Hirayama S, Yamazaki H, Kanaki T, Takahashi K, et al. LR11, a mosaic LDL receptor family member, mediates the uptake of ApoE-rich lipoproteins in vitro. Arterioscler Thromb Vasc Biol. 2001;21:1501-6 pubmed
  11. Taylor D, Hooper N. The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein. Biochem J. 2007;402:17-23 pubmed
    ..We show also that another LRP1 ligand that can cause neurodegenerative disease, the Alzheimer's amyloid precursor protein, does not modulate the endocytosis of PrP(C). ..
  12. Kerr M, Gasperini R, Gibbs M, Hou X, Shepherd C, Strickland D, et al. Inhibition of Abeta aggregation and neurotoxicity by the 39-kDa receptor-associated protein. J Neurochem. 2010;112:1199-209 pubmed publisher
    ..RAP also blocked an Abeta-induced inhibition of long-term memory consolidation in 1-day-old chicks. This study demonstrates that RAP binds to Abeta and is an inhibitor of the neurotoxic effects of Abeta. ..
  13. Atkinson J, Harroun T, Wassall S, Stillwell W, Katsaras J. The location and behavior of alpha-tocopherol in membranes. Mol Nutr Food Res. 2010;54:641-51 pubmed publisher
    ..Physical methodologies are then described to elucidate the nature of the interaction of alpha-tocopherol with PUFA and to establish that the vitamin and PUFA-containing phospholipids co-localize in non-raft domains. ..
  14. Lisi S, Chiovato L, Pinchera A, Marcocci C, Menconi F, Morabito E, et al. Impaired thyroglobulin (Tg) secretion by FRTL-5 cells transfected with soluble receptor associated protein (RAP): evidence for a role of RAP in the Tg biosynthetic pathway. J Endocrinol Invest. 2003;26:1105-10 pubmed
    ..Therefore, we concluded that RAP is involved in Tg secretion by FRTL-5 cells suggesting that RAP may function as a Tg molecular chaperone. ..
  15. Shibata Y, Muramatsu T, Hirai M, Inui T, Kimura T, Saito H, et al. Nuclear targeting by the growth factor midkine. Mol Cell Biol. 2002;22:6788-96 pubmed
    ..This study therefore reveals a novel role of LRP in intracellular signaling by its ligand and the importance of nucleolin in this process. ..
  16. Schwarz H, Lenting P, Binder B, Mihaly J, Denis C, Dorner F, et al. Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice. Blood. 2000;95:1703-8 pubmed
    ..These findings suggest that the accelerated clearance of factor VIII seen in the absence of vWF may be a result of the involvement of LRP in factor VIII metabolism. (Blood. 2000;95:1703-1708) ..
  17. Lillis A, Van Duyn L, Murphy Ullrich J, Strickland D. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev. 2008;88:887-918 pubmed publisher
  18. Zhang C, Yang T, Wang J, Liu G, Chen Q. The Chinese traditional medicine 'Bushen Yinao Pian' increased the level of ageing-related gene LRPAP-1 expression in the cerebral tissue of accelerated senescence-prone mouse 8/Ta. J Ethnopharmacol. 2005;98:61-5 pubmed
    ..It indicated that the Chinese traditional medicine 'Bushen Yinao Pian' plays an important role in anti-ageing by increasing LRPAP-1 expression level. ..
  19. Herz J. The switch on the RAPper's necklace. Mol Cell. 2006;23:451-5 pubmed
    ..Two recent papers in Molecular Cell by Fisher et al. (2006) and Lee et al. (2006) reveal a novel mechanism by which one of these chaperones, the receptor-associated protein RAP, accomplishes this task. ..
  20. Ting H, Stice J, Schaff U, Hui D, Rutledge J, Knowlton A, et al. Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha. Circ Res. 2007;100:381-90 pubmed
  21. Furukawa T, Ozawa M, Huang R, Muramatsu T. A heparin binding protein whose expression increases during differentiation of embryonal carcinoma cells to parietal endoderm cells: cDNA cloning and sequence analysis. J Biochem. 1990;108:297-302 pubmed
    ..We propose that HBP-44 is extruded from plasma membranes and interacts with heparin and related molecules and that it is involved in the interactions of plasma membranes with basement membranes. ..
  22. Chen X, Ma X, Ma S, Coenraads P, Zhang C, Liu J, et al. Proteomic analysis of the rat ovary following chronic low-dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). J Toxicol Environ Health A. 2009;72:717-26 pubmed publisher
    ..Data provide further insight into the mechanisms by which TCDD disrupts ovarian function by indicating which differential protein expressions following low-dose TCDD exposure. ..
  23. Nielsen P, Ellgaard L, Etzerodt M, Thogersen H, Poulsen F. The solution structure of the N-terminal domain of alpha2-macroglobulin receptor-associated protein. Proc Natl Acad Sci U S A. 1997;94:7521-5 pubmed
    ..The amino acid residues known to form the epitope are in a helix-loop-helix conformation, and from the structure it is possible to rationalize the published results obtained from studies of fragments of the N-terminal domain. ..
  24. Mantuano E, Jo M, Gonias S, Campana W. Low density lipoprotein receptor-related protein (LRP1) regulates Rac1 and RhoA reciprocally to control Schwann cell adhesion and migration. J Biol Chem. 2010;285:14259-66 pubmed publisher
    ..The effects of LRP1 gene-silencing and RAP implicate autocrine pathways involving endogenously produced LRP1 ligands. Regulation of Schwann cell migration by LRP1 may be important in PNS injury. ..
  25. Dixit M, Choudhuri G, Keshri L, Mittal B. Association of low density lipoprotein receptor related protein-associated protein (LRPAP1) gene insertion/deletion polymorphism with gallstone disease. J Gastroenterol Hepatol. 2006;21:847-9 pubmed
    ..24% and 23.76% in controls, respectively. Frequency of I allele was significantly higher in the patient group than in the control group (P = 0.003). In the present study I (insertion) allele was found to be associated with GSD. ..
  26. Li Y, Chen J, Lu W, McCormick L, Wang J, Bu G. Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding. J Cell Sci. 2005;118:5305-14 pubmed
    ..Together our results show that in addition to serving as a folding chaperone, Mesd can function as a receptor antagonist by inhibiting ligand binding to mature LRP6. ..
  27. Harris H, Kasravi F. Lipoprotein-bound LPS induces cytokine tolerance in hepatocytes. J Endotoxin Res. 2003;9:45-50 pubmed
  28. Kinoshita A, Whelan C, Smith C, Mikhailenko I, Rebeck G, Strickland D, et al. Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: role of the intracellular adapter protein Fe65. J Neurosci. 2001;21:8354-61 pubmed
    ..These findings demonstrate that LRP interaction with APP occurs via both extracellular and intracellular protein interaction domains. ..
  29. Robert J, Ramanayake T, Maniero G, Morales H, Chida A. Phylogenetic conservation of glycoprotein 96 ability to interact with CD91 and facilitate antigen cross-presentation. J Immunol. 2008;180:3176-82 pubmed
    ..The persistence of this biological process for >350 million years that separate mammals and amphibians from a common ancestor strongly supports the proposition that gp96 and CD91 are critically involved in immune surveillance. ..
  30. Gonzalez P, Alvarez R, Reguero J, Batalla A, Alvarez V, Cortina A, et al. Variation in the lipoprotein receptor-related protein, alpha2-macroglobulin and lipoprotein receptor-associated protein genes in relation to plasma lipid levels and risk of early myocardial infarction. Coron Artery Dis. 2002;13:251-4 pubmed
    ..0065; odds ratio = 2.18, 95% confidence intervals = 1.22-3.90). According to our data, the variation at the LRPAP1 gene could contribute to the risk of developing an early episode of MI. ..
  31. Shirotani Ikejima H, Kokame K, Hamuro T, Bu G, Kato H, Miyata T. Tissue factor pathway inhibitor induces expression of JUNB and GADD45B mRNAs. Biochem Biophys Res Commun. 2002;299:847-52 pubmed
    ..In conclusion, this is the first report to show an effect of TFPI on mRNA expression, and suggests that TFPI modulates cellular functions by inducing JUNB and GADD45B expression through binding to VLDL-R. ..
  32. Nakamoto M, Ozawa M, Jacinto S, Furukawa T, Natori Y, Shirahama H, et al. Mouse heparin binding protein-44 (HBP-44) associates with brushin, a high-molecular-weight glycoprotein antigen common to the kidney and teratocarcinomas. J Biochem. 1993;114:344-9 pubmed
  33. Pandey P, Pradhan S, Mittal B. LRP-associated protein gene (LRPAP1) and susceptibility to degenerative dementia. Genes Brain Behav. 2008;7:943-50 pubmed publisher
    ..0001, OR =5.35). Our study suggests that LRPAP1-D and APOE E4 alleles significantly increase the susceptibility to degenerative dementias. ..
  34. Santovito A, Bulgarello C, Cervella P, Bigatti M, Delpero M. Allelic frequencies at the ACE and LRPAP1 loci suggest age-related relationships in a northern Italian population. Ann Hum Biol. 2007;34:102-6 pubmed
    ..02) and between the first and the third age group (p < 0.01), with the 51-79 age group showing the higher D/D and the lower I/D genotype frequency values. ..
  35. Lisi S, Botta R, Pinchera A, Di Cosmo C, Perri A, De Marco G, et al. Sequencing of the entire coding region of the receptor associated protein (RAP) in patients with primary hypothyroidism of unknown origin. J Endocrinol Invest. 2007;30:839-43 pubmed
  36. Zhuo M, Holtzman D, Li Y, Osaka H, DeMaro J, Jacquin M, et al. Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. J Neurosci. 2000;20:542-9 pubmed
    ..Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP. ..
  37. Kounnas M, Argraves W, Strickland D. The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, alpha 2-macroglobulin receptor and glycoprotein 330. J Biol Chem. 1992;267:21162-6 pubmed
    ..The functional significance of RAP binding to gp330 may be to antagonize ligand binding as has been demonstrated for the alpha 2MR/LRP or to assist in the biosynthetic processing and/or trafficking of this receptor. ..
  38. McCormick L, Urade R, Arakaki Y, Schwartz A, Bu G. Independent and cooperative roles of N-glycans and molecular chaperones in the folding and disulfide bond formation of the low-density lipoprotein (LDL) receptor-related protein. Biochemistry. 2005;44:5794-803 pubmed
  39. Yagyu H, Lutz E, Kako Y, Marks S, Hu Y, Choi S, et al. Very low density lipoprotein (VLDL) receptor-deficient mice have reduced lipoprotein lipase activity. Possible causes of hypertriglyceridemia and reduced body mass with VLDL receptor deficiency. J Biol Chem. 2002;277:10037-43 pubmed
    ..Therefore, the VLDLr is required for normal LpL regulation in vivo, and the disruption of VLDLr results in hypertriglyceridemia associated with decreased LpL activity. ..
  40. Noguchi T, Noguchi M, Masubuchi H, Seki T, Ariga T. IL-1beta down-regulates tissue-type plasminogen activator by up-regulating low-density lipoprotein receptor-related protein in AML 12 cells. Biochem Biophys Res Commun. 2001;288:42-8 pubmed
    ..The receptor-mediated endocytosis of tPA by hepatocytes may thus play a crucial role in the down-regulation of fibrinolysis during the acute-phase response. ..
  41. Falnes PØ -, Wesche J, Olsnes S. Ability of the Tat basic domain and VP22 to mediate cell binding, but not membrane translocation of the diphtheria toxin A-fragment. Biochemistry. 2001;40:4349-58 pubmed
    ..The data indicate that transport of dtA into the cell by the TAT-peptide and VP22 is inefficient. ..
  42. Xu G, Karch C, Li N, Lin N, Fromholt D, Gonzales V, et al. Receptor-associated protein (RAP) plays a central role in modulating Abeta deposition in APP/PS1 transgenic mice. PLoS ONE. 2008;3:e3159 pubmed publisher
    ..Together, these findings suggest a central role for RAP in Alzheimer amyloidogenesis. ..
  43. Zhang J, Zhang H, Bi H, Liu Z, Guo J, Qu S. Optimal expression condition of recombinant RAP. J Huazhong Univ Sci Technolog Med Sci. 2007;27:5-8 pubmed
    ..It was concluded that the expression condition of recombinant RAP was optimized and functional RAP was obtained, which offered a good foundation for the further production of RAP as research tool. ..
  44. Zeiner M, Gehring U. A protein that interacts with members of the nuclear hormone receptor family: identification and cDNA cloning. Proc Natl Acad Sci U S A. 1995;92:11465-9 pubmed
    ..e., release from heat shock proteins. The sequence identified here appears to be a general partner protein for nuclear hormone receptors, with the gene being expressed in a variety of mammalian tissues. ..
  45. Makoveichuk E, Castel S, Vilaró S, Olivecrona G. Lipoprotein lipase-dependent binding and uptake of low density lipoproteins by THP-1 monocytes and macrophages: possible involvement of lipid rafts. Biochim Biophys Acta. 2004;1686:37-49 pubmed
    ..Dimeric and monomeric LPL differ in their ability to mediate binding/uptake of LDL, probably due to different mechanisms for binding/internalization. ..
  46. Pan W, Kastin A, Zankel T, van Kerkhof P, Terasaki T, Bu G. Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier. J Cell Sci. 2004;117:5071-8 pubmed
    ..These studies suggest that RAP may provide a novel means of protein-based drug delivery to the brain. ..
  47. Meijer A, Rohlena J, van der Zwaan C, van Zonneveld A, Boertjes R, Lenting P, et al. Functional duplication of ligand-binding domains within low-density lipoprotein receptor-related protein for interaction with receptor associated protein, alpha2-macroglobulin, factor IXa and factor VIII. Biochim Biophys Acta. 2007;1774:714-22 pubmed
    ..The results imply that there is an internal functional duplication of complement-type repeats within LRP resulting in two clusters that bind the same ligands. ..
  48. Brownley K, Hurwitz B. Assessment of autonomic and cardiovascular function in HIV disease. Adv Cardiol. 2003;40:105-39 pubmed
  49. Lakkaraju A, Rahman Y, Dubinsky J. Low-density lipoprotein receptor-related protein mediates the endocytosis of anionic liposomes in neurons. J Biol Chem. 2002;277:15085-92 pubmed
    ..Thus, constitutive endocytosis of anionic liposomes by LRP utilizes only one component, in contrast to the more involved heparan sulfate proteoglycan-LRP pathway implicated in the pathogenesis of Alzheimer's disease. ..
  50. Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, Gonias S, et al. The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J Neurosci. 2008;28:11571-82 pubmed publisher
    ..These results establish LRP-1 as a cell-signaling receptor for MMP-9, which may be significant in regulating Schwann cell migration and physiology in PNS injury. ..
  51. Yamauchi K, Tozuka M, Hidaka E, Ueno I, Matsuda K, Katsuyama T. Internalization of beta-amyloid causes downregulation of apolipoprotein E mRNA expression in neuroblastoma cells. Ann Clin Lab Sci. 2003;33:68-78 pubmed
    ..A disorder of this physiological response could be linked to the development of AD. ..
  52. Bu G, Maksymovitch E, Geuze H, Schwartz A. Subcellular localization and endocytic function of low density lipoprotein receptor-related protein in human glioblastoma cells. J Biol Chem. 1994;269:29874-82 pubmed
    ..Our results thus strongly suggest several potential roles for LRP in brain protein and lipoprotein metabolism, as well as control of extracellular protease activity. ..
  53. Bacic D, Capuano P, Gisler S, Pribanic S, Christensen E, Biber J, et al. Impaired PTH-induced endocytotic down-regulation of the renal type IIa Na+/Pi-cotransporter in RAP-deficient mice with reduced megalin expression. Pflugers Arch. 2003;446:475-84 pubmed
    ..In contrast, both wildtype and RAP-deficient mice were able to adapt to high-, normal, and low-P(i) diets appropriately as indicated by urinary P(i) excretion and NaP(i)-IIa protein abundance. ..