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Rapid Generation of Amyloid from Native Proteins In vitro
05:48

Rapid Generation of Amyloid from Native Proteins In vitro

Published on: December 5, 2013

Functional amyloidogenesis and cytotoxicity-insights into biology and pathology

Douglas M Fowler1, Jeffery W Kelly

  • 1Department of Genome Sciences, University of Washington, Seattle, Washington, USA. dfowler@uw.edu

Plos Biology
|January 10, 2013
PubMed

Insights

Prions like [Het-s] in fungi cause cell death by forming amyloid aggregates. This study reveals how [Het-s] amyloid triggers a conformational change in Het-S protein, leading to membrane pore formation and cell death.

Area of Science:

  • Mycology
  • Structural Biology
  • Cell Biology

Background:

  • Prions are self-templating proteins capable of inter-organismal transfer.
  • The [Het-s] prion in Podospora anserina is a functional amyloid involved in heterokaryon incompatibility.
  • Incompatibility involves cell death upon fusion of [Het-s] prion strains with Het-S expressing strains.

Purpose of the Study:

  • To elucidate the mechanism of cell death mediated by the [Het-s] prion and Het-S protein interaction.
  • To understand how functional amyloid aggregates initiate cytotoxicity.

Main Methods:

  • Investigated the structural and functional consequences of [Het-s] and Het-S C-terminal domain co-amyloidogenesis.
  • Analyzed conformational changes in the Het-S protein, including N-terminal HeLo domain rearrangements.
  • Examined the formation of transmembrane helices and subsequent pore formation.

Main Results:

  • Co-amyloidogenesis of Het-s and Het-S C-terminal domains induces significant conformational changes in the Het-S N-terminal HeLo domain.
  • This rearrangement exposes a transmembrane helix within Het-S.
  • Oligomerization of these helices leads to pore formation, cytosolic leakage, and cell death.

Conclusions:

  • The [Het-s] prion orchestrates programmed cytotoxicity by inducing a conformational change in Het-S, compromising membrane integrity.
  • This mechanism expands the known functions of amyloid proteins beyond simple aggregation.
  • The cell-killing mechanism may share similarities with pathological amyloid-induced tissue demise.

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