Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4

Angela Jen, Celia J. Parkyn, Roy C. Mootoosamy, Melanie J. Ford, Alice Warley, Qiang Liu, Guojun D Bu, Ilia V. Baskakov, Søren Moestrup, Lindsay McGuinness, Nigel Emptage, Roger J. Morris

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

For infectious prion protein (designated PrPSc) to act as a template to convert normal cellular protein (PrPC) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrPC is the low-density lipoprotein receptor-related protein 1 (LRP1). We show here that on sensory neurons LRP1 is also the receptor that binds and rapidly endocytoses smaller oligomeric forms of infectious prion fibrils, and recombinant PrP fibrils. Although LRP1 binds two molecules of most ligands independently to its receptor clusters 2 and 4, PrPC and PrPSc fibrils bind only to receptor cluster 4. PrPSc fibrils out-compete PrPC for internalization. When endocytosed, PrPSc fibrils are routed to lysosomes, rather than recycled to the cell surface with PrPC. Thus, although LRP1 binds both forms of PrP, it traffics them to separate fates within sensory neurons. The binding of both to ligand cluster 4 should enable genetic modification of PrP binding without disrupting other roles of LRP1 essential to neuronal viability and function, thereby enabling in vivo analysis of the role of this interaction in controlling both prion and LRP1 biology.

Original languageEnglish (US)
Pages (from-to)246-255
Number of pages10
JournalJournal of Cell Science
Volume123
Issue number2
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Lipoprotein Receptors
Prions
Endocytosis
Sensory Receptor Cells
Proteins
PrPC Proteins
Ligands
Lysosomes
Recombinant Proteins
Protein Binding
Prion Proteins

Keywords

  • Endocytosis
  • LRP1
  • Lysosome
  • Neuron
  • Prion protein

ASJC Scopus subject areas

  • Cell Biology

Cite this

Jen, A., Parkyn, C. J., Mootoosamy, R. C., Ford, M. J., Warley, A., Liu, Q., ... Morris, R. J. (2010). Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4. Journal of Cell Science, 123(2), 246-255. https://doi.org/10.1242/jcs.058099

Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4. / Jen, Angela; Parkyn, Celia J.; Mootoosamy, Roy C.; Ford, Melanie J.; Warley, Alice; Liu, Qiang; Bu, Guojun D; Baskakov, Ilia V.; Moestrup, Søren; McGuinness, Lindsay; Emptage, Nigel; Morris, Roger J.

In: Journal of Cell Science, Vol. 123, No. 2, 2010, p. 246-255.

Research output: Contribution to journalArticle

Jen, A, Parkyn, CJ, Mootoosamy, RC, Ford, MJ, Warley, A, Liu, Q, Bu, GD, Baskakov, IV, Moestrup, S, McGuinness, L, Emptage, N & Morris, RJ 2010, 'Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4', Journal of Cell Science, vol. 123, no. 2, pp. 246-255. https://doi.org/10.1242/jcs.058099
Jen, Angela ; Parkyn, Celia J. ; Mootoosamy, Roy C. ; Ford, Melanie J. ; Warley, Alice ; Liu, Qiang ; Bu, Guojun D ; Baskakov, Ilia V. ; Moestrup, Søren ; McGuinness, Lindsay ; Emptage, Nigel ; Morris, Roger J. / Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4. In: Journal of Cell Science. 2010 ; Vol. 123, No. 2. pp. 246-255.
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