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Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
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Crystallographic studies of prion protein (PrP) segments suggest how structural changes encoded by polymorphism at

Marcin I Apostol1, Michael R Sawaya, Duilio Cascio

  • 1Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-DOE Institute, UCLA, Los Angeles, California 90095-1570, USA.

The Journal of Biological Chemistry
|August 6, 2010
PubMed

Insights

A common genetic variation in the human prion gene (codon 129) influences prion disease susceptibility. Structural analysis of prion protein segments reveals how methionine or valine at residue 129 impacts disease risk.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • A single nucleotide polymorphism (SNP) at codon 129 of the human prion gene affects prion disease susceptibility.
  • The molecular mechanisms underlying this genetic influence on prion protein (PrP) function remain unclear.

Purpose of the Study:

  • To elucidate the structural basis of how codon 129 polymorphism influences prion disease.
  • To investigate the role of methionine (Met) and valine (Val) at residue 129 in PrP structure and interactions.

Main Methods:

  • Determined crystal structures of 6-residue prion protein segments containing either Met or Val at residue 129.
  • Analyzed the structure of "homozygous steric zippers" formed by these segments.
  • Developed a structure-based model for the heterozygous Met-Val steric zipper.

Main Results:

  • Crystal structures revealed that PrP segments form "steric zippers" through interacting beta-sheets.
  • Direct intermolecular interactions between Met or Val residues in opposing sheets were observed in homozygous zippers.
  • These structural findings provide a basis for understanding the impact of the codon 129 polymorphism.

Conclusions:

  • The study provides structural insights into how the codon 129 polymorphism in the prion gene affects prion protein interactions.
  • These findings offer a molecular explanation for the observed variations in prion disease susceptibility and progression.
  • Structural data supports the role of residue 129 variants in modulating prion disease pathogenesis.

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