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Protein Misfolding Cyclic Amplification of Prions
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Protein Misfolding Cyclic Amplification of Prions

Published on: November 7, 2012

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Cofactor molecules induce structural transformation during infectious prion formation

Michael B Miller1, Daphne W Wang, Fei Wang

  • 1Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.

Structure (London, England : 1993)
|October 15, 2013
PubMed

Insights

Cofactor molecules induce major structural changes during prion formation. This dynamic process, studied using deuterium exchange mass spectrometry, results in biologically active prions from recombinant PrP.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Structural Biology

Background:

  • Misfolded proteins spread in neurodegenerative diseases.
  • Mammalian prions are uniquely infectious in vitro.
  • Prion formation involves complex protein conformational changes.

Purpose of the Study:

  • To investigate stepwise protein conformational changes during prion formation.
  • To understand the role of cofactors (POPG and RNA) in prion genesis.
  • To elucidate the structural pathway from recombinant PrP to infectious PrP(Sc).

Main Methods:

  • Generation of infectious prions de novo from purified recombinant PrP.
  • Utilizing deuterium exchange mass spectrometry (DXMS) to monitor conformational changes.
  • Employing specific conversion cofactors: palmitoyl-oleoyl-phosphatidylglycerol (POPG) and RNA.

Main Results:

  • POPG induced significant structural alterations in PrP, affecting α helices and β strands.
  • RNA addition led to increased exposure of the PrP N terminus.
  • Conversion to infectious PrP(Sc) showed decreased solvent exposure but retained cofactor-induced features.

Conclusions:

  • Cofactor molecules initiate major structural rearrangements in PrP.
  • Prion formation is a dynamic sequence of conformational changes.
  • These cofactor-driven changes are critical for generating biologically active prions.

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