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High-throughput Screening for Protein-based Inheritance in S. cerevisiae
Published on: August 8, 2017
Highly promiscuous nature of prion polymerization
Natallia Makarava1, Cheng-I Lee, Valeriy G Ostapchenko
1Medical Biotechnology Center, University of Maryland Biotechnology Institute, Department of Biochemistry and Molecular Biology, Baltimore 21201, USA.
The Journal of Biological Chemistry
|October 18, 2007
Summary
Prion protein (PrP) polymerization shows no species specificity. In vitro, mouse and hamster PrP fibrils efficiently use both homologous and heterologous substrates, challenging the role of primary structure in prion transmission barriers.
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- The species barrier in prion transmission is thought to be primarily determined by the prion protein's (PrP) primary structure.
- However, the influence of prion strains on this barrier complicates the direct attribution to PrP sequence differences between species.
Purpose of the Study:
- To investigate the intrinsic polymerization properties of mouse and hamster recombinant PrPs.
- To determine if PrP primary structure dictates species specificity in amyloid fibril formation and elongation in the absence of cellular factors.
Main Methods:
- Analyzed spontaneous polymerization of full-length mouse and hamster recombinant PrPs into amyloid conformations.
- Conducted cross-seeding polymerization assays using mixtures of homologous and heterologous PrP variants.
- Examined individual fibril elongation patterns (unidirectional and bidirectional).
Main Results:
- No evidence of species specificity was observed in cross-seeding polymerization assays.
- Preformed mouse or hamster PrP fibrils equally incorporated both homologous and heterologous PrP substrates during elongation.
- PrP fibrils demonstrated intrinsic promiscuity, efficiently utilizing heterologous PrP variants without strain-specific templates or cellular modifications.
Conclusions:
- In vitro, prion protein amyloid fibrils are intrinsically promiscuous and can accommodate sequence variations.
- The self-propagating activity of amyloid fibrils is not strictly limited by species-specific primary structures, suggesting other factors may be more critical for the in vivo prion transmission barrier.
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