Structures and Activities of Prions and Prion Proteins

Caughey, Byron

Abstract

Understanding the structure of PrPSc and its strain variation has been one of the major challenges in prion disease biology. To study the strain-dependent conformations of PrPSc, we purified proteinase-resistant PrPSc (PrPRES) from mouse brains with three different murine-adapted scrapie strains (Chandler, 22L, and Me7) and systematically tested the accessibility of epitopes of a wide range of anti-PrP and anti-PrPSc-specific antibodies by indirect-ELISA. We found that epitopes of most anti-PrP antibodies were hidden in the folded structure of PrPRES even though these epitopes are revealed with guanidine-denaturation. However, reactivities to a PrPSc-specific conformational C-terminal antibody showed significant differences among the three different prion strains. Our results provide evidence for strain-dependent conformational variation near the C-termini of molecules within PrPSc multimers.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIAAI000580-27
• Application #: 9354718
• Support Year: 27
• Fiscal Year: 2016

Institution

• Name: Niaid Extramural Activities

Publications

Groveman, Bradley R; Raymond, Gregory J; Campbell, Katrina J et al. (2017) Role of the central lysine cluster and scrapie templating in the transmissibility of synthetic prion protein aggregates. PLoS Pathog 13:e1006623

Kraus, Allison; Raymond, Gregory J; Race, Brent et al. (2017) PrP P102L and Nearby Lysine Mutations Promote Spontaneous In Vitro Formation of Transmissible Prions. J Virol 91:

Cracco, Laura; Notari, Silvio; Cali, Ignazio et al. (2017) Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type. Sci Rep 7:38280

Wang, Fei; Wang, Xinhe; Orrú, Christina D et al. (2017) Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity. PLoS Pathog 13:e1006491

Bett, Cyrus; Lawrence, Jessica; Kurt, Timothy D et al. (2017) Enhanced neuroinvasion by smaller, soluble prions. Acta Neuropathol Commun 5:32

Hughson, Andrew G; Race, Brent; Kraus, Allison et al. (2016) Inactivation of Prions and Amyloid Seeds with Hypochlorous Acid. PLoS Pathog 12:e1005914

Alibhai, James; Blanco, Richard A; Barria, Marcelo A et al. (2016) Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration. PLoS Biol 14:e1002579

Saijo, Eri; Hughson, Andrew G; Raymond, Gregory J et al. (2016) PrPSc-Specific Antibody Reveals C-Terminal Conformational Differences between Prion Strains. J Virol 90:4905-13

Kraus, Allison; Anson, Kelsie J; Raymond, Lynne D et al. (2015) Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation. J Biol Chem 290:21510-22

Groveman, Bradley R; Kraus, Allison; Raymond, Lynne D et al. (2015) Charge neutralization of the central lysine cluster in prion protein (PrP) promotes PrP(Sc)-like folding of recombinant PrP amyloids. J Biol Chem 290:1119-28