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 Bu, Ilia V Baskakov, Søren Moestrup, Lindsay McGuinness, Nigel Emptage, Roger J Morris

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

For infectious prion protein (designated PrP(Sc)) to act as a template to convert normal cellular protein (PrP(C)) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrP(C) 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, PrP(C) and PrP(Sc) fibrils bind only to receptor cluster 4. PrP(Sc) fibrils out-compete PrP(C) for internalization. When endocytosed, PrP(Sc) fibrils are routed to lysosomes, rather than recycled to the cell surface with PrP(C). 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.

OriginalsprogEngelsk
TidsskriftJournal of Cell Science
Vol/bind123
Udgave nummerPt 2
Sider (fra-til)246-55
Antal sider10
ISSN0021-9533
DOI
StatusUdgivet - 15. jan. 2010

Fingeraftryk

Low Density Lipoprotein Receptor-Related Protein-1
Prions
Endocytosis
Lipoprotein Receptors
Protein C
Proteins
Sensory Receptor Cells
Ligands

Emneord

  • Animals
  • Cells, Cultured
  • Endocytosis
  • Endosomes
  • Ligands
  • Lysosomes
  • Mice
  • Mice, Inbred C57BL
  • Peptide Hydrolases
  • PrPC Proteins
  • PrPSc Proteins
  • Prions
  • Protein Binding
  • Protein Structure, Secondary
  • Receptors, LDL
  • Sensory Receptor Cells
  • Tumor Suppressor Proteins

Citer dette

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(Pt 2), 246-55. https://doi.org/10.1242/jcs.058099
Jen, Angela ; Parkyn, Celia J ; Mootoosamy, Roy C ; Ford, Melanie J ; Warley, Alice ; Liu, Qiang ; Bu, Guojun ; 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. I: Journal of Cell Science. 2010 ; Bind 123, Nr. Pt 2. s. 246-55.
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title = "Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4",
abstract = "For infectious prion protein (designated PrP(Sc)) to act as a template to convert normal cellular protein (PrP(C)) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrP(C) 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, PrP(C) and PrP(Sc) fibrils bind only to receptor cluster 4. PrP(Sc) fibrils out-compete PrP(C) for internalization. When endocytosed, PrP(Sc) fibrils are routed to lysosomes, rather than recycled to the cell surface with PrP(C). 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.",
keywords = "Animals, Cells, Cultured, Endocytosis, Endosomes, Ligands, Lysosomes, Mice, Mice, Inbred C57BL, Peptide Hydrolases, PrPC Proteins, PrPSc Proteins, Prions, Protein Binding, Protein Structure, Secondary, Receptors, LDL, Sensory Receptor Cells, Tumor Suppressor Proteins",
author = "Angela Jen and Parkyn, {Celia J} and Mootoosamy, {Roy C} and Ford, {Melanie J} and Alice Warley and Qiang Liu and Guojun Bu and Baskakov, {Ilia V} and S{\o}ren Moestrup and Lindsay McGuinness and Nigel Emptage and Morris, {Roger J}",
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Jen, A, Parkyn, CJ, Mootoosamy, RC, Ford, MJ, Warley, A, Liu, Q, Bu, G, 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, bind 123, nr. Pt 2, s. 246-55. 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; Baskakov, Ilia V; Moestrup, Søren; McGuinness, Lindsay; Emptage, Nigel; Morris, Roger J.

I: Journal of Cell Science, Bind 123, Nr. Pt 2, 15.01.2010, s. 246-55.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4

AU - Jen, Angela

AU - Parkyn, Celia J

AU - Mootoosamy, Roy C

AU - Ford, Melanie J

AU - Warley, Alice

AU - Liu, Qiang

AU - Bu, Guojun

AU - Baskakov, Ilia V

AU - Moestrup, Søren

AU - McGuinness, Lindsay

AU - Emptage, Nigel

AU - Morris, Roger J

PY - 2010/1/15

Y1 - 2010/1/15

N2 - For infectious prion protein (designated PrP(Sc)) to act as a template to convert normal cellular protein (PrP(C)) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrP(C) 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, PrP(C) and PrP(Sc) fibrils bind only to receptor cluster 4. PrP(Sc) fibrils out-compete PrP(C) for internalization. When endocytosed, PrP(Sc) fibrils are routed to lysosomes, rather than recycled to the cell surface with PrP(C). 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.

AB - For infectious prion protein (designated PrP(Sc)) to act as a template to convert normal cellular protein (PrP(C)) to its distinctive pathogenic conformation, the two forms of prion protein (PrP) must interact closely. The neuronal receptor that rapidly endocytoses PrP(C) 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, PrP(C) and PrP(Sc) fibrils bind only to receptor cluster 4. PrP(Sc) fibrils out-compete PrP(C) for internalization. When endocytosed, PrP(Sc) fibrils are routed to lysosomes, rather than recycled to the cell surface with PrP(C). 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.

KW - Animals

KW - Cells, Cultured

KW - Endocytosis

KW - Endosomes

KW - Ligands

KW - Lysosomes

KW - Mice

KW - Mice, Inbred C57BL

KW - Peptide Hydrolases

KW - PrPC Proteins

KW - PrPSc Proteins

KW - Prions

KW - Protein Binding

KW - Protein Structure, Secondary

KW - Receptors, LDL

KW - Sensory Receptor Cells

KW - Tumor Suppressor Proteins

U2 - 10.1242/jcs.058099

DO - 10.1242/jcs.058099

M3 - Journal article

VL - 123

SP - 246

EP - 255

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - Pt 2

ER -