Skip to main content
SpringerLink
Log in

Role of the Ldl Receptor-Related Protein in Proteinase and Lipoprotein Catabolism

  • Chapter
Cardiovascular Disease

Abstract

Proteinases play an important role in biological processes and consequently their activity is carefully regulated. This often occurs by reaction of the proteolytic enzyme with specific inhibitors. Removal of the inhibited proteinase is then accomplished by its interaction with cell surface receptors which mediate its internalization and subsequent degradation. The LDL receptor-related protein/α2M receptor (LRP) is large cell surface receptor that mediates the removal of proteinases and proteinase-inhibitor complexes1–5. In addition, this receptor plays an important role in the hepatic clearance of certain apolipoprotein E- and lipoprotein lipase-enriched lipoproteins6–8. Thus, LRP serves a unique role in biology by virtue of its capacity to mediate the cellular uptake of both proteinases and lipoproteins.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ashcom J D, Tiller S E, Dickerson K, Cravens J L, Argraves W S, Strickland D K. The human α2 macroglobulin receptor: identification of a 420-kD cell surface glycoprotein specific for the activated conformation of α2-macroglobulin. J Cell Biol 1990; 110: 1041–1048.

    Article  PubMed  CAS  Google Scholar 

  2. Kounnas M Z, Henkin J, Argraves W S, Strickland D K. Low density lipoprotein receptor-related protein/α2-macroglobulin receptor mediates cellular uptake of pro-urokinase. J Biol Chem 1993; 268: 21862–21867.

    PubMed  CAS  Google Scholar 

  3. Bu G, Williams S, Strickland D K, Schwartz A L. Low density lipoprotein receptor-related protein/α2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Nat! Acad Sci USA 1992; 89: 7427–7431.

    Article  PubMed  CAS  Google Scholar 

  4. Nykjær A, Petersen C M, Moller B, Jensen P H, Moestrup S K, Holtet T L, Etzerodt M, Thogersen H C, Munch M, Andreasen P A, Gliemann J. Purified α2-macroglobulin receptor/LDL receptor-related protein binds urokinase•plasminogen activator inhibitor type-1 complex. Evidence that the α2 macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem 1992; 267: 14543–14546.

    PubMed  Google Scholar 

  5. Orth K, Madison E L, Gething M -J, Sambrook J F, Herz J. Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/α2-macroglobulin receptor. Proc Natl Acad Sci USA 1992; 89: 7422–7426.

    Article  PubMed  CAS  Google Scholar 

  6. Kowal R C, Herz J, Goldstein J L, Esser V, Brown M S. Low Density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci USA 1989; 86: 5810–5814.

    Article  PubMed  CAS  Google Scholar 

  7. Beisiegel U, Weber W, Ihrke G, Herz J, Stanley K K. The LDL-receptor related protein, LRP, is an apolipoprotein E binding protein. Nature 1989; 341: 162–164.

    CAS  Google Scholar 

  8. Chappell D A, Fry G L, Waknitz M A, Muhonen L E, Pladet M W, Iverius P -H, Strickland D K. Lipoprotein lipase induces catabolism of normal triglyceride-rich lipoproteins via the low density lipoprotein receptor-related protein/α2-macroglobulin receptor in vitro. A process facilitated by cell-surface proteoglycans. JBiol Chem 1993; 268: 14168–14175.

    CAS  Google Scholar 

  9. Yamamoto T, Davis G C, Brown M S, Schneider W J, Casey M L, Goldstein J L, Russel D W. The human LDL receptor: A cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 1984; 39: 27–38.

    Article  PubMed  CAS  Google Scholar 

  10. Chen W-J, Goldstein J L, Brown M S. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. JBiol Chem 1990; 265: 3116–3123.

    CAS  Google Scholar 

  11. Davis C G, Goldstein J L, Sudhof T C, Anderson R G W, Russell D W, Brown M S. Acid-dependent ligand dissociation and recylcing of LDL receptor mediated by growth factor homology region. Nature 1987; 326: 760–765.

    Article  PubMed  CAS  Google Scholar 

  12. Russell D W, Brown M S, Goldstein J L. Different combinations of cyteine-rich repeats mediate binding of LDL receptor to different proteins. JBiol Chem 1989; 264: 21682–21688.

    CAS  Google Scholar 

  13. Takahashi S, Kawarabayasi Y, Nakai T, Sakai J, Yamamoto T. Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc Natl Acad Sci USA 1992; 89: 9252–9256.

    Article  PubMed  CAS  Google Scholar 

  14. Sakai J, Hoshino A, Takahashi S, Miura Y, Ishii H, Suzuki H, Kawarabayasi Y, Yamamoto T. Structure, Chromosome Location, and Expression of the human very low density lipoprotein receptor gene. JBiol Chem 1994; 269: 2173–2182.

    CAS  Google Scholar 

  15. Sudhof T C, Goldstein J L, Brown M S, Russell D W. The LDL receptor gene: A mosaic of exons shared with different proteins. Science 1985; 228: 815–822.

    Article  PubMed  CAS  Google Scholar 

  16. Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley K K. Surface location and high affinity for calcium of a 500kDa liver membrane protein closely related to the LDL-receptor suggest a physiolocical role as lipoprotein receptor. EMBO. 1988; 7: 4119–4127.

    CAS  Google Scholar 

  17. Herz J, Kowal R C, Goldstein J L, Brown M S. Proteolytic processing of the 600 kD low density liprotein receptor related protein LRP occurs in a trans-Golgi compartment. EMBO J 1990; 9: 1769–1776.

    PubMed  CAS  Google Scholar 

  18. Kerjaschki D, Farquhar M G. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci USA 1982; 79: 5557–5561.

    Article  PubMed  CAS  Google Scholar 

  19. Kounnas M Z, Strickland D K, Argraves W S. Glycoprotein 330, a member of the LDL receptor family, binds lipoprotein lipase In Vitro. JBiol Chem 1993; 268: 14176–14181.

    CAS  Google Scholar 

  20. Korenberg J R, Argraves K M, Chen X-N, Tran H, Strickland D K, Argraves W S. Chromosomal Localization of Human Genes for the LDL Receptor Family Member Glycoprotien 330 and its Associated Protein RAP. Genomics 1994; 22: 88–93

    Article  PubMed  CAS  Google Scholar 

  21. Barber D L, Sanders E J, Aebersold R, Schneider W J. The receptor for yolk lipoprotein deposition in the chicken oocyte. JBiol Chem 1991; 266: 18761–18770.

    CAS  Google Scholar 

  22. Brown M S, Goldstein J L. A receptor-Mediated Pathway for Cholesterol Homeostasis. Science 1986; 232: 34–47.

    Article  PubMed  CAS  Google Scholar 

  23. Willnow T E, Goldstein J L, Orth K, Brown M S, Herz J. LDL receptor related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. JBiol Chem 1992; 267: 26172–26180.

    CAS  Google Scholar 

  24. Zheng G, Bachinsky D R, Stamenkovic I, Strickland D K, Brown D, Andres G, McCluskey R T. Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/α2macroglobulin receptor, and the receptor-associated protein (RAP). JHistochem Cytochem 1994; 42: 531–542.

    Article  CAS  Google Scholar 

  25. Roldan A L, Cubellis M V, Masucci M T, Behrendt N, Lund L R, Dan, K, Appella E, Blasi F. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis EMBO J 1990; 9: 467–474.

    PubMed  CAS  Google Scholar 

  26. Ploug M, Ronne E, Behrendt N, Jensen A L, Blasi F, Dano K. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. JBiol Chem 1991; 266: 1926–1933.

    CAS  Google Scholar 

  27. Ellis V, Dano K. The urokinase receptor and the regulation of cell surface plasminogen activation. Fibrinolysis 1992; 6 Suppl. 4: 27–34.

    CAS  Google Scholar 

  28. Blasi F. Urokinase and Urokinase receptor: A paracrine/autocrine system regulating cell migration and invasiveness. BioEssays 1993; 15: 105–111.

    Article  Google Scholar 

  29. Cubellis M V, Wun T C, Blasi F. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PM-1. EMBO J 1990; 9: 1079–1085.

    PubMed  CAS  Google Scholar 

  30. Jensen P H, Moestrup S K, Gliemann J. Purification of the human placental α2-macroglobulin receptor. FEBS Lett 1989; 255: 275–280.

    Article  PubMed  CAS  Google Scholar 

  31. Williams S E, Ashcom J D, Argraves W S, Strickland D K. A novel mechanism for controlling the activity of α2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein. JBiol Chem 1992; 267: 9035–9040.

    CAS  Google Scholar 

  32. Kounnas M Z, Argraves W S, Strickland D K. The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, α2-macroglobulin receptor and glycoprotein 330. JBiol Chem 1992; 267: 21162–21166.

    CAS  Google Scholar 

  33. Battey F, Gafvels M E, Fitzgerald D J, Argraves W S, Chappell D A, Strauss III J F, Strickland D K. The 39 kDa Receptor Associated Protein Regulates Ligand Binding by the Very Low Density Lipoprotein Receptor. JBiol Chem 1994; in press

    Google Scholar 

  34. Medh J D, Fry G L, Bowen S L, Pladet M W, Strickland D K, Chappell D A. The 39 kDa Receptor-Associated Protein Modulates Lipoprotein Catabolism by Binding to LDL receptors. JBiol Chem 1994; submitted

    Google Scholar 

  35. Yayon A, Klagsbrun M, Esko J D, Leder P, Ornitz D M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 1991; 64: 841–848.

    Article  PubMed  CAS  Google Scholar 

  36. Nilsson-Ehle P, Garfinkel, A.S., and Schotz, M.C. AnnuRevBiochem 1980; 49: 667–693.

    CAS  Google Scholar 

  37. Auwerx J, Leroy P, Schoonjans K. Lipoprotein lipase: Recent contributions from molecular biology. Crit Rev Clin Lab Sci 1992; 29: 243–268.

    Article  PubMed  CAS  Google Scholar 

  38. Goldstein, J.L. and Brown, M.S. Familiar hypercholesterolemia. In: The Metabolic Basis of Inherited Disease, edited by Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. New York: McGraw-Hill Publishing Company, 1989, p. 1215–1250.

    Google Scholar 

  39. Felts J M, Itakura H, Crane R T. The mechanism of assimilation of constituents of chylomicrons, VLDL and remnants. Biochem Biophys Res Comm 1975; 66: 1467–1475.

    Article  PubMed  CAS  Google Scholar 

  40. Beisiegel U, Weber W, Bengtsson-Olivecrona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Natl Acad Sci USA 1991; 88: 8342–8346.

    Article  PubMed  CAS  Google Scholar 

  41. Chappell D A, Fry G L, Waknitz M A, Iverius P -H, Williams S E, Strickland D K. The low density lipoprotein receptor-related protein/α2 macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase. JBiol Chem 1992; 267: 25764–25767.

    CAS  Google Scholar 

  42. Eisenberg S, Sehayek E, Olivecrona T, Vlodaysky I. Lipoprotein lipase enhances bindng of lipoproteins to Heparin Sulfate on Cell Surfaces and Extracellular Matrix. J Clinlnvest 1992; 90: 2013–2021.

    CAS  Google Scholar 

  43. Williams K J, Fless G M, Petrie K A, Snyder M L, Brocia R W, Swenson T L. Mechanism by which lipoprotein lipase alters cellular metabolism of lipoprotein(a), LDL, and nascent lipoproteins. JBiol Chem 1992; 267: 13284–13292.

    CAS  Google Scholar 

  44. Iverius P-H, Ostlund-Lindqvist A M. LPL from bovine milk. Isolation procedure, chemical characterization and molecular weight analysis. J Biol Chem 1976; 251: 7791–7795.

    PubMed  CAS  Google Scholar 

  45. Osborne J C, Bengtsson-Olivecrona G, Lee N S, Olivecrona T. Studies on Inactivation of lipoprotein lipase: Role of the dimer to monomer dissociation. Biochemistry 1985; 24: 5606–5611.

    Article  PubMed  CAS  Google Scholar 

  46. Winkler F K, D’Arcy, A., and Hunziker, W. Structure of human pancreatic lipase. Nature 1990; 343: 771–774.

    Article  PubMed  CAS  Google Scholar 

  47. van Tilbeurgh H, Roussel A, Lalouel J-M, Cambillau C. Lipoprotein Lipase. Molecular Model Based on the Pancreatic Lipase X-Ray Structure: Consequences for heparin binding and Catalysis. JBiol Chem 1994; 269: 4626–4633.

    Google Scholar 

  48. Williams S E, Inoue I, Tran H, Fry G L, Pladet M W, Iverius P-H, Lalouel J-M, Chappell D A, Strickland D K. The Carboxyl-terminal Domain of Lipoprotein Lipase Binds to the Low Density Lipoprotein Receptor-related Protein/α2Macroglobulin receptor (LRP) and mediates Binding of Normal Very Low Density Lipoproteins to LRP. J Biol Chem 1994; 269: 8653–8658.

    CAS  Google Scholar 

  49. Sottrup-Jensen L, Gliemann J, Van Leuven F. Domain structure of human α2-macroglobulin: characterization of a receptor-binding domain obtained by digestion with papain. FEBS 1986; 205: 20–24.

    Article  CAS  Google Scholar 

  50. Jinno Y, Chaudhary V K, Kondo T, Adhya S, Fitzgerald D J, Pastan I. Mutational analysis of Domain I of Pseudomonas Exotoxin A. J Biol Chem 1988; 263: 13203–13207.

    CAS  Google Scholar 

  51. Kounnas M Z, Haudenschild C C, Strickland D K, Argraves W S. Immunological Localization of glycoprotein 330, Low Density Lipoprotein Receptor Related Protein and 39 kDa Receptor Associated Protein in Embryonic Mouse Tissue. In Vivo 1994; in press:

    Google Scholar 

  52. Luoma J, Hiltunen T, Särkioja T, Moestrup S K, Gliemann J, Kodama T, Nikkari T, Ylä-Herttuala S. Expression of α2 macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions. J Clin Invest 1994; 93: 2014–2021.

    Article  PubMed  CAS  Google Scholar 

  53. Chappell, D.A., Inoue, I., Fry, G.L., Pladet, M.W., Bowen, S.L., Iverius, P-H, Lalouel, J-M., and Strickland, D.K. Cellular catabolism of Normal Very Low Density Lipoproteins via the Low Density Lipoprotein Receptor-related Protein/α2 Macroglobulin receptor is Induced by the C-terminal domain of lipoprotein lipase. J. Biol. Chem. 1994;269: 18001–18006

    PubMed  CAS  Google Scholar 

  54. Willnow T E, Sheng Z, Ishibashi S, Herz J. Inhibition of Hepatic Chylomicron Remnant Uptake by Gene Transfer of a Receptor Antagonist. Science 1994; in press

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biochemistry Department, Holland Laboratory, American Red Cross, Rockville, MD, 20855, USA

    Dudley K. Strickland, Suzanne E. Williams, Maria Z. Kounnas & W. Scott Argraves

  2. Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah, 84132, USA

    Ituro Inoue & Jean-Marc Lalouel

  3. Department of Medicine, University of Iowa, Iowa City, Iowa, 52242, USA

    David A. Chappell

Authors
  1. Dudley K. Strickland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suzanne E. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Z. Kounnas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Scott Argraves
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ituro Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Marc Lalouel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David A. Chappell
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. The George Washington University Medical Center, Washington, D.C., USA

    Linda L. Gallo

Rights and permissions

Reprints and permissions

Copyright information

© 1995 Springer Science+Business Media New York

About this chapter

Cite this chapter

Strickland, D.K. et al. (1995). Role of the Ldl Receptor-Related Protein in Proteinase and Lipoprotein Catabolism. In: Gallo, L.L. (eds) Cardiovascular Disease. GWUMC Department of Biochemistry Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1959-1_29

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-1959-1_29

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5805-3

  • Online ISBN: 978-1-4615-1959-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation