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The role of conformational flexibility in prion propagation and maintenance for Sup35p

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Abstract

The [PSI+] factor of Saccharomyces cerevisiae is a protein-based genetic element (prion) comprised of a heritable altered conformation of the cytosolic translation termination factor Sup35p. In vitro, the prion-determining region (NM) of Sup35p undergoes conformational conversion from a highly flexible soluble state to structured amyloid fibers, with a rate that is greatly accelerated by preformed NM fiber nuclei. Nucleated conformational conversion is the molecular basis of the genetic inheritance of [PSI+] and provides a new model for studying amyloidogenesis. Here we investigate the importance of structure and structural flexibility in soluble NM. Elevated temperatures, chemical chaperones and certain mutations in NM increase or change its structural content and inhibit or enhance nucleated conformational conversion. We propose that the structural flexibility of NM is particularly suited to allowing heritable protein-based changes in cellular behavior.

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Figure 1: Comparison of NMwt purified under denaturing and nondenaturing conditions.
Figure 2: Influences of temperature and chemical chaperones on NMwt secondary structure.
Figure 3: Influences of temperature and chemical chaperones on NMwt (10 μM) quaternary structure.
Figure 4: Influences of temperature and chemical chaperones on nucleated conformational conversion of NMwt (5 μM) in the presence of sonicated preformed NMwt fibers (5 % w/w) and monitored by CR binding.
Figure 5: Mutations in the oligopeptide repeats of NM influence structure and conformational conversion.

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Acknowledgements

This research was supported by the National Institutes of Health, the Howard Hughes Medical Institute, the Keck Foundation, the University of Chicago Materials Research Science and Engineering Center and a postdoctoral fellowship of the Deutsche Forschungsgemeinschaft (T.S.). We gratefully acknowledge A. Kowal for Electron Microscopy, G. Sawicki for Atomic Force Microscopy, J.-J. Liu and H.-C. Chang for sharing unpublished results, J. Frederikson and J. Rehm for experimental help, and J. Bloom, M. Duennwald, T.F. Outeiro and H. True-Knob for comments on the manuscript.

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  1. Howard Hughes Medical Institute and Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, 60637, Illinois, USA

    Thomas Scheibel & Susan L. Lindquist

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  1. Thomas Scheibel
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  2. Susan L. Lindquist
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Correspondence to Susan L. Lindquist.

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Scheibel, T., Lindquist, S. The role of conformational flexibility in prion propagation and maintenance for Sup35p. Nat Struct Mol Biol 8, 958–962 (2001). https://doi.org/10.1038/nsb1101-958

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