Abstract
Prions are thought to consist of infectious proteins that cause transmissible spongiform encephalopathies1. According to overwhelming evidence, the pathogenic prion protein PrPSc converts its host encoded isoform PrPc into insoluble aggregates of PrPSc, concomitant with pathological modifications (for review, see refs. 1–3). Although the physiological role of PrPc is poorly understood4, studies with PrP knockout mice demonstrated that PrPc is required for the development of prion diseases5. Using the yeast two-hybrid technology in Saccharomyces cerevisiae, we identified the 37-kDa laminin receptor precursor (LRP) as interacting with the cellular prion protein PrPc. Mapping analysis of the LRP–PrP interaction site in S. cerevisiae revealed that PrP and laminin share the same binding domain (amino acids 161 to 180)6 on LRP. The LRP–PrP interaction was confirmed in vivo in insect (Sf9) and mammalian cells (COS-7). The LRP level was increased in scrapie-infected murine N2a cells and in brain and spleen of scrapie-infected mice. In contrast, the LRP concentration was not significantly altered in these organs from mice infected with the bovine spongiform encephalopathic agent (BSE), which have a lower PrPSc accumulation. LRP levels, however, were dramatically increased in brain and pancreas, slightly increased in the spleen and not altered in the liver of scrapie-infected hamsters. These data show that enhanced LRP concentrations are correlated with PrPSc accumulation in organs from mice and hamsters. The laminin receptor precursor, which is highly conserved among mammals and is located on the cell surface, may act as a receptor or co-receptor for the prion protein on mammalian cells.
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References
Prusiner, S.B. Molecular biology of prion diseases. Science 252, 1515–1522 (1991).
Weissmann, C. Molecular biology of prion diseases. Trends Cell. Biol. 4, 10–14 (1994).
Edenhofer, F., Weiss, S., Winnacker, E.-L. & Famulok, M. Chemistry and molecular biology of transmissible spongiform encephalopathies. Angew. Chem. Int. Ed. Engl. 36, 1674–1694 (1997).
Borchelt, D.R. & Sisodia, S.S. Loss of functional prion protein: A role in prion disorders? Chem. Biol. 3, 619–621 (1996).
Bueler, H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993).
Castronovo, V., Taraboletti, G. & Sobel, M.E. Functional domains of the 67-kDa laminin receptor precursor. J. Biol. Chem. 266, 20440–6 (1991).
Edenhofer, F. et al. Prion protein PrPc interacts with molecular chaperones of the Hsp60 family. J. Virol. 70, 4724–4728 (1996).
Mecham, R.P. Receptors for laminin on mammalian cells. FASEB J. 5, 2538–2546 (1991).
Rao, C.N. et al. Evidence for a precursor of the high-affinity metastasis-associated murine laminin receptor. Biochemistry 28, 7476–7486 (1989).
Yow, H. et al. increased mRNA expression of a laminin-binding protein in human colon carcinoma: Complete sequence of a full-length cDNA encoding the protein. Proc. Natl. Acad. Sci. USA 85, 6394–6398 (1988).
Malinoff, H.L. & Wicha, M.S. Isolation of a cell surface receptor for laminin from murinefibrosarcoma cells. Biochem. Biophys. Res. Commun. 111, 804–808 (1983).
Lesot, H., Kühl, U. & von der Mark, K., Isolation of a laminin binding protein from muscle cell membranes. EMBO J. 2, 861–865 (1983).
Rao, N.C., Barsky, S.H., Terranova, V.P. & Liotta, L.A. Isolation of a tumor cell laminin receptor. Biochem. Biophys. Res. Commun. 111, 804–808 (1983).
Castronovo, V. et al. Biosynthesis of the 67 kDa high affinity laminin receptor. Biochem. Biophys. Res. Commun. 177, 177–83 (1991).
Landowski, T.H., Dratz, E.A. & Starkey, J.R. Studies of the structure of the metastasisassociated 67 kDa laminin binding protein: Fatty acid acylation and evidence supporting dimerization of the 32 kDa gene product to form the mature protein. Biochemistry 34, 11276–11287 (1995).
Jackers, P. et al. Seventeen copies of the human 37-kDa laminin receptor precur-sor/p40 ribosome-associated protein gene are processed pseudogenes arisen from retropositional events. Biochim. Biophys. Acta 1305, 98–104 (1996).
Jackers, P. et al. Isolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21.3. Oncogene 13, 495–503 (1996).
Weiss, S., Rieger, R., Edenhofer, F., Fisch, E. & Winnacker, E.-L. Recombinant prion protein rPrP27-30 from Syrian Golden hamster reveals proteinase K sensitivity. Biochem. Biophys. Res. Commun. 219, 173–179 (1996).
Weiss, S. et al. Overexpression of active Syrian Golden hamster prion protein PrPc as a glutathione S-transferase fusion in heterologous systems. J. Virol. 69, 4776–4783 (1995).
Beck, K., Hunter, I. & Engel, J. Structure and function of laminin: Anatomy of a multidomain glycoprotein. FASEB J. 4, 148–160 (1990).
Lasmézas, C.I. et al. Strain specific and common pathogenic events in murine models of scrapie and bovine spongiform encephalopathy. J. Gen. Virol. 77, 1601–1609 (1996).
Jendroska, K. et al. Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity. Neurology 41, 1482–1490 (1991).
Kimberlin, R.H. & Walker, C.A. Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J. Gen. Virol. 67, 255–263 (1986).
Rubenstein, R. et al. Scrapie-infected spleens: Analysis of infectivity, scrapieassociated fibrils, and protease-resistant proteins. J. Infect. Dis. 164, 29–35 (1991).
Farquhar, C.F. et al. Protease-resistant PrP deposition in brain and non-central nervous system tissues of a murine model of bovine spongiform encephalopathy. J. Gen. Virol. 77, 1941–1946 (1996).
Ye, X., Carp, R.I. & Kascsak, R.J. Histopathological changes in the islets of Langerhans in scrapie 139H-affected hamsters. J. Comp. Pathol. 110, 153–167 (1994).
Albelda, S.M. & Buck, C.A. Integrins and other cell adhesion molecules. FASEB J. 4, 2868–2880 (1990).
Hinek, A., Wrenn, D.S., Mecham, R.P. & Barondes, S.H. The elastin receptor: A galactoside binding protein. Science 239, 1539–1541 (1988).
Hunter, D.D., Shah, V., Merlie, J.P. & Sanes, J.R. A laminin-like adhesive protein concentrated in the synaptic cleft of the neuromuscular junction. Nature 338, 229–234 (1989).
Wewer, U.M. et al. Altered levels of laminin receptor mRNA in various human carcinoma cells that have different abilities to bind laminin. Proc. Natl. Acad. Sci. USA 83, 7137–7141 (1986).
Keppel, E. & Schaller, H.C. A 33 kDa protein with sequence homology to the ‘laminin binding protein’ is associated with the cytoskeleton in hydra and in mammalian cells. J. Cell. Science 100, 789–797 (1991).
Demianova, M., Formosa, T.G. & Ellis, S.R. Yeast proteins related to the p40/iaminin receptor precursor are essential components of the 40 S ribosomal subunit. J. Biol. Chem. 271, 11383–11391 (1996).
Ouzounis, C., Kyrpides, N. & Sander, C. Novel protein families in archaean genomes. Nucleic Acids Res. 23, 565–570 (1995).
Wang, K.-S., Kuhn, R.J., Strauss, E.G., Ou, S. & H, S.J., High affinity laminin receptor is a receptor for Sindbis virus in mammalian cells. J. Virol. 66, 4992–5001 (1992).
Ludwig, G.V., Kondig, J.P. & Smith, J.F. A putative receptor for Venezuelan equine encephalitis virus from mosquito cells. J. Virol. 70, 5592–5599 (1996).
Douville, P.J., Harvey, W.I. & Carbonetto, S. Isolation and partial characterization of high affinity laminin receptor in neural cells. J. Biol. Chem. 263, 14964–14969 (1988).
Stahl, N. et al. Structural studies of the scrapie prion protein using mass spectrometry and amino acid sequencing. Biochemistry 32, 1991–2002 (1993).
Wendler, W., Altmann, H. & Winnacker, E.-L. Transcriptional activation of NFI/CTF1 depends on a sequence motif strongly related to the carboxy terminal domain of RNA polymerase II. Nucleic Acids Res. 1994, 2601–2603 (1994).
Gyuris, J., Golemis, E., Chertkov, H. & Brent, R., Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell 75, 791–803 (1993).
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Rieger, R., Edenhofer, F., Lasmézas, C. et al. The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells. Nat Med 3, 1383–1388 (1997). https://doi.org/10.1038/nm1297-1383
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DOI: https://doi.org/10.1038/nm1297-1383
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