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Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain
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Published on: October 3, 2012

Surface charge of polyoxometalates modulates polymerization of the scrapie prion protein

Holger Wille1, Maheswaran Shanmugam, Muralee Murugesu

  • 1Institute for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143, USA. hwille@ind.ucsf.edu

Proceedings of the National Academy of Sciences of the United States of America
|February 19, 2009
PubMed

Insights

Polyoxometalates (POMs) influence prion protein (PrP 27-30) polymerization. Keggin-type POMs with specific heteroatoms and negative charges dictate whether prion rods or 2D crystals form, impacting prion structure.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Materials Science

Background:

  • Prions are infectious agents composed of misfolded prion proteins (PrPSc).
  • N-terminally truncated PrPSc (PrP 27-30) forms amyloid rods and retains infectivity.
  • Understanding PrP polymerization is crucial for prion disease research.

Purpose of the Study:

  • To investigate the role of polyoxometalates (POMs) in directing PrP 27-30 polymerization.
  • To determine how POM structure, specifically Keggin-type POMs, influences the formation of prion rods versus 2D crystals.
  • To explore the potential of POMs for creating ordered PrP structures for study.

Main Methods:

  • Utilized various Keggin-type polyoxometalates (POMs) to induce polymerization of PrP 27-30.
  • Analyzed the resulting structures (prion rods vs. 2D crystals) using electron microscopy and antibody binding assays.
  • Varied the central heteroatom and charge density of POMs to observe effects on PrP assembly.

Main Results:

  • Specific Keggin-type POMs promoted the formation of either prion rods or 2D crystals of PrP 27-30.
  • POMs with low-charge densities (e.g., phosphotungstate) favored prion rod formation.
  • POMs with higher negative charges (e.g., boron or hydrogen heteroatoms) promoted the assembly of well-ordered 2D crystals.
  • Antibody binding indicated conformational changes in PrP 27-30 upon 2D crystal formation, especially after urea treatment.

Conclusions:

  • The negative charge of Keggin-type POMs is a key determinant of PrP 27-30 quaternary structure.
  • POMs offer a method for selectively producing ordered 2D PrP crystals, superior to existing techniques.
  • Further research is needed to elucidate the precise mechanisms by which POMs modulate prion polymerization pathways.

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