Self-perpetuating changes in Sup35 protein conformation as a mechanism of heredity in yeast

Tricia R. Serio, Anil G. Cashikar, Anthony S. Kowal, George J. Sawicki, Susan L. Lindquist

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Recently, a novel mode of inheritance has been described in the yeast Saccharomyces cervisiae. The mechanism is based on the prion hypothesis, which posits that self-perpetuating changes in the conformation of single protein, PrP, underlie the severe neurodegeneration associated with the transmissible spongi-form enchephalopathies in mammals. In yeast, two prions, [URE3] and [PSI+], have been identified, but these factors confer unique phenotypes rather than disease to the organism. In each case, the prion-associated phenotype has been linked to alternative conformations of the Ure2 and Sup35 proteins. Remarkably, Ure2 and Sup35 proteins existing in the alternative conformations have the unique capacity to transmit this physical state to the newly synthesized protein in vivo. Thus, a mechanism exists to ensure replication of the conformational information that underlies protein-only inheritance. We have characterized the mechanism by which Sup35 conformational information is replicated in vitro. The assembly of amyloid fibres by a region of Sup35 encompassing the N-terminal 254 amino acids faithfully recapitulates the in vivo propagation of [PSI+]. Mutations that alter [PSI+] inheritance in vivo change the kinetics of amyloid assembly in vitro in a complementary fashion, and lysates from [PSI+] cells, but not [psi-] cells, accelerate assembly in vitro. Using this system we propose a mechanism by which the alternative conformation of Sup35 is adopted by an unstructured oilgomeric intermediate at the time of assembly.

Original languageEnglish (US)
Pages (from-to)35-43
Number of pages9
JournalBiochemical Society Symposium
Volume68
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Biochemistry

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