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Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain
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Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain

Published on: October 3, 2012

Oligomerization of the human prion protein proceeds via a molten globule intermediate

Remo Gerber1, Abdessamad Tahiri-Alaoui, P J Hore

  • 1Department of Chemistry, University of Oxford, Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford OX1 3QZ, United Kingdom. remo.gerber@chem.ox.ac.uk

The Journal of Biological Chemistry
|January 11, 2007
PubMed

Insights

Prion protein misfolding, crucial in disease, does not start with beta-sheet structures. Instead, an alpha-helical precursor with molten globule traits initiates the conversion to beta-oligomers.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • Prion diseases involve the human prion protein (PrP) misfolding from alpha-helical to beta-sheet structures.
  • The exact molecular mechanisms and intermediate states of PrP misfolding are not well understood.
  • Amyloid fibrils, characteristic of prion diseases, are insoluble, hindering detailed study.

Purpose of the Study:

  • To investigate the misfolding mechanism of the human prion protein (PrP).
  • To characterize the structural properties of the beta-oligomer, a misfolded PrP isoform.
  • To identify the nature of the precursor state in PrP misfolding.

Main Methods:

  • Solution-state Nuclear Magnetic Resonance (NMR) spectroscopy was employed.
  • The study focused on the beta-oligomer, a partially proteinase-resistant misfolded PrP isoform.
  • Analysis of the transient monomeric precursor state was performed.

Main Results:

  • The beta-oligomer, sharing properties with amyloid, was successfully studied using solution-state NMR.
  • Evidence was found for an alpha-helical, molten globule-like monomeric precursor, not a beta-sheet precursor.
  • A mechanism involving intermolecular contacts triggering beta-oligomer formation was proposed.

Conclusions:

  • The human prion protein beta-oligomer forms from an alpha-helical precursor, not a beta-sheet precursor.
  • Misfolding is initiated by a partially unfolded, alpha-helical state with molten globule characteristics.
  • This finding challenges previous assumptions about prion protein misfolding pathways.

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