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Short disordered protein segment regulates cross-species transmission of a yeast prion

Toshinobu Shida1,2, Yuji O Kamatari3,4, Takao Yoda5,6

  • 1Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.

Nature Chemical Biology
|April 15, 2020
PubMed

Insights

Structural fluctuations in host prion proteins regulate cross-species transmission. A specific disordered segment conformation, identified using NMR and simulations, governs this process, offering insights into prion diseases.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • Prion diseases involve the misfolding and aggregation of prion proteins.
  • Cross-species prion transmission occurs when soluble prions encounter foreign aggregates.
  • The role of host prion protein structural dynamics in transmission efficiency is not well understood.

Purpose of the Study:

  • To investigate how structural fluctuations of host soluble prion protein regulate cross-species prion transmission.
  • To identify specific protein segments and residues critical for interspecies prion transmissibility.

Main Methods:

  • Utilized two distantly related yeast prion Sup35 proteins.
  • Employed a multidisciplinary approach including high-resolution Nuclear Magnetic Resonance (NMR) and molecular dynamics simulations.
  • Analyzed in vitro and in vivo prion transmission models.

Main Results:

  • Identified a specific conformation of a short disordered segment that governs interspecies prion transmissibility.
  • Pinpointed critical residues within this segment that modulate prion protein dynamics and conformation.
  • Demonstrated that subtle conformational differences, like a methylene group, significantly impact cross-seeding activity.

Conclusions:

  • Conformational dynamics of short segments in host prion proteins are key regulators of cross-species transmission.
  • Mechanistic insights into prion cross-seeding between heterologous proteins were uncovered.
  • Findings provide a basis for understanding prion disease transmission and developing therapeutic strategies.

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