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Originally published in Science Express on 20 May 2004
Science 18 June 2004:
Vol. 304. no. 5678, pp. 1793 - 1797
DOI: 10.1126/science.1098007
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Reports

Hsp104 Catalyzes Formation and Elimination of Self-Replicating Sup35 Prion Conformers

James Shorter and Susan Lindquist*

The protein-remodeling factor Hsp104 governs inheritance of [PSI+], a yeast prion formed by self-perpetuating amyloid conformers of the translation termination factor Sup35. Perplexingly, either excess or insufficient Hsp104 eliminates [PSI+]. In vitro, at low concentrations, Hsp104 catalyzed the formation of oligomeric intermediates that proved critical for the nucleation of Sup 35 fibrillization de novo and displayed a conformation common among amyloidogenic polypeptides. At higher Hsp104 concentrations, amyloidogenic oligomerization and contingent fibrillization were abolished. Hsp104 also disassembled mature fibers in a manner that initially exposed new surfaces for conformational replication but eventually exterminated prion conformers. These Hsp104 activities differed in their reaction mechanism and can explain [PSI+] inheritance patterns.

Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed. E-mail: lindquist_admin{at}wi.mit.edu

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