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A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers

Geoffrey P Noble1, Daphne W Wang2, Daniel J Walsh1

  • 1Departments of Biochemistry and Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

Plos Pathogens
|July 1, 2015
PubMed

Insights

Infectious prions require specific structural conformations for infectivity. Researchers found that recombinant prions lacking the ability to interact with GPI-anchored PrPC are not infectious, highlighting key structural determinants of prion disease.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Structural Biology

Background:

  • Infectious prions are misfolded prion proteins (PrPSc) that propagate themselves.
  • The protein-only hypothesis predicts autocatalytic PrPSc is infectious.
  • Recombinant PrPSc infectivity determinants remain unclear.

Purpose of the Study:

  • Identify structural and functional features linked to prion infectivity.
  • Compare infectious and non-infectious recombinant PrP conformers.
  • Elucidate the role of specific PrPSc conformations in infectivity.

Main Methods:

  • Hydrogen/deuterium exchange mass spectrometry (DXMS) to assess solvent accessibility.
  • Raman spectroscopy and immunoprecipitation to analyze protein conformation.
  • In vitro prion propagation assays using mouse PrPC substrates.

Main Results:

  • Infectious and non-infectious PrP conformers showed similar protease-resistant cores but differed in solvent accessibility in residues 91-115 and 144-163.
  • Distinct conformations were observed in these domains between infectious and non-infectious conformers.
  • The non-infectious conformer failed to seed mouse PrPC substrates with GPI anchors.

Conclusions:

  • A specific conformation enabling interaction with post-translationally modified PrPC is crucial for recombinant prion infectivity.
  • Discrete structural features within PrPSc are associated with biological infectivity.
  • These findings advance understanding of prion propagation mechanisms.

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