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Strain conformation, primary structure and the propagation of the yeast prion [PSI+]

Katherine J Verges1, Melanie H Smith, Brandon H Toyama

  • 1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA.

Nature Structural & Molecular Biology
|March 23, 2011
PubMed

Insights

Prion protein sequence impacts strain propagation. A specific mutation (PNM2) affects yeast prion (Sup35) conformations differently, highlighting the importance of particle delivery during cell division for prion inheritance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Yeast Genetics

Background:

  • Prion proteins are known to adopt diverse infectious conformations, referred to as strains.
  • The yeast [PSI(+)] prion protein, Sup35, serves as a model system to study prion propagation and strain diversity.
  • Understanding how protein sequence variations influence prion strain propagation is crucial for deciphering prion biology.

Purpose of the Study:

  • To investigate the impact of a specific prion protein mutation (PNM2) on the propagation of distinct yeast prion (Sup35) conformations (Sc4 and Sc37).
  • To elucidate the mechanisms by which sequence alterations affect prion strain stability, replication, and inheritance.

Main Methods:

  • Utilized two distinct infectious conformations of the yeast prion Sup35: Sc4 and Sc37.
  • Introduced a G58D point mutant (PNM2) of Sup35 to assess its effects on prion propagation.
  • Analyzed the structural integrity, growth kinetics, division mechanisms, and cellular delivery of prion particles.

Main Results:

  • The PNM2 mutation caused rapid, recessive loss of the Sc4 prion conformation but did not interfere with Sc37 propagation.
  • PNM2 destabilized the amyloid core of Sc37, leading to slower growth but enhanced prion division and robust propagation.
  • PNM2 did not alter Sc4 structure or division but impeded its delivery to daughter cells, impacting inheritance.

Conclusions:

  • Prion protein sequence critically influences the propagation of specific prion strains.
  • Effective delivery of infectious prion particles during cell division is a vital, conformation-dependent step in prion inheritance.
  • The PNM2 mutation reveals distinct mechanisms by which sequence affects prion propagation, emphasizing the role of cellular processes beyond protein structure.

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