Structural evidence for the critical role of the prion protein hydrophobic region in forming an infectious prion.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
05
06
2019
accepted:
09
10
2019
revised:
19
12
2019
pubmed:
10
12
2019
medline:
29
2
2020
entrez:
10
12
2019
Statut:
epublish
Résumé
Prion or PrPSc is the proteinaceous infectious agent causing prion diseases in various mammalian species. Despite decades of research, the structural basis for PrPSc formation and prion infectivity remains elusive. To understand the role of the hydrophobic region in forming infectious prion at the molecular level, we report X-ray crystal structures of mouse (Mo) prion protein (PrP) (residues 89-230) in complex with a nanobody (Nb484). Using the recombinant prion propagation system, we show that the binding of Nb484 to the hydrophobic region of MoPrP efficiently inhibits the propagation of proteinase K resistant PrPSc and prion infectivity. In addition, when added to cultured mouse brain slices in high concentrations, Nb484 exhibits no neurotoxicity, which is drastically different from other neurotoxic anti-PrP antibodies, suggesting that the Nb484 can be a potential therapeutic agent against prion disease. In summary, our data provides the first structure-function evidence supporting a crucial role of the hydrophobic region of PrP in forming an infectious prion.
Identifiants
pubmed: 31815959
doi: 10.1371/journal.ppat.1008139
pii: PPATHOGENS-D-19-01017
pmc: PMC6922452
doi:
Substances chimiques
PrPSc Proteins
0
Prion Proteins
0
Prnp protein, mouse
0
Single-Domain Antibodies
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008139Subventions
Organisme : NINDS NIH HHS
ID : R01 NS060729
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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