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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

Elongated oligomers assemble into mammalian PrP amyloid fibrils

M Howard Tattum1, Sara Cohen-Krausz, Kanjana Thumanu

  • 1MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.

Journal of Molecular Biology
|February 14, 2006
PubMed

Insights

Researchers studied the structure of misfolded prion protein (PrP) amyloid fibrils. They discovered a hierarchical assembly mechanism involving two intertwined protofilaments, revealing key structural features of these disease-associated protein aggregates.

Area of Science:

  • Structural Biology
  • Neuroscience
  • Biochemistry

Background:

  • Prion diseases involve the misfolding of the mammalian prion protein (PrP) into beta-rich amyloid fibrils.
  • Understanding the structure of these misfolded PrP aggregates is crucial for elucidating prion disease mechanisms.

Purpose of the Study:

  • To determine the three-dimensional structure of recombinant mouse PrP amyloid fibrils.
  • To investigate the assembly mechanism and structural characteristics of PrP amyloid formation.

Main Methods:

  • Recombinant mouse PrP (residues 91-231) was used to grow beta-form amyloid fibrils.
  • Electron microscopy and 3D image processing were employed to generate density maps of the fibrils.
  • Immunological reactivity was compared to ex vivo PrPSc.

Main Results:

  • Two forms of PrP fibrils with distinct helical twists were characterized.
  • Fibrils consist of two intertwined protofilaments, each with a subunit repeat of approximately 60 Å.
  • A hierarchical assembly mechanism involving elongated PrP oligomers was suggested, with flexible crossbridges observed.

Conclusions:

  • The study provides high-resolution structural insights into PrP amyloid fibrils.
  • The findings reveal a specific hierarchical assembly pathway for PrP, beyond the generic cross-beta amyloid fold.
  • The structural details may inform the development of therapeutic strategies for prion diseases.

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