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Emerging principles of conformation-based prion inheritance.
Peter Chien1, Jonathan S Weissman, Angela H DePace
1Graduate Group in Biophysics, Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94107-2240, USA. pchien@fas.harvard.edu
Annual Review of Biochemistry
|June 11, 2004
Summary
The prion hypothesis explains how proteins can be infectious agents. Misfolded proteins, or prions, can adopt multiple conformations, explaining distinct strains and transmission barriers between species.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- The prion hypothesis posits proteins as infectious agents, initially for transmissible spongiform encephalopathies (TSEs).
- Prions are now recognized in fungi, causing non-Mendelian traits through heritable protein conformational changes.
- Amyloid-like aggregates, rich in beta-sheets, are central to prion propagation in both mammals and yeast.
Purpose of the Study:
- To explore universal features of prion infection and inheritance.
- To explain prion strains and transmission barriers using physical properties of amyloid aggregates.
- To investigate how protein misfolding into multiple conformations underlies prion diversity.
Main Methods:
- Focus on physical properties of amyloid-like aggregates.
- Discuss mechanistic parallels between mammalian and yeast prion phenomena.
- Analyze the role of protein misfolding and conformational changes.
Main Results:
- Prion strains and interspecies transmission barriers may arise from a protein's ability to adopt multiple self-propagating conformations.
- Single mutations can alter the spectrum of favored misfolded conformations.
- Changes in amyloid conformation influence propagation specificity and strain phenotypes.
Conclusions:
- A unified model explains prion inheritance and features of diseases involving toxic protein aggregates.
- Understanding protein misfolding is key to deciphering prion biology.
- The study highlights the physical basis of protein-based inheritance and infectivity.