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Nucleation-dependent conformational conversion of the Y145Stop variant of human prion protein: structural clues for

Bishwajit Kundu1, Nilesh R Maiti, Eric M Jones

  • 1Department of Physiology and Biophysics, Case Western Reserve University, 3109 Adelbert Road, Cleveland, OH 44106, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 2, 2003
PubMed

Insights

The Y145Stop mutation in human prion protein (PrP) causes disease. This study shows the Y145Stop PrP fragment spontaneously forms amyloid fibrils, with residues 138-141 being critical for this process.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • The Tyr to Stop codon mutation at position 145 (Y145Stop) in human prion protein (PrP) is linked to Gerstmann-Straussler-Scheinker-like disease.
  • This mutation leads to extensive amyloid deposits in the brain, a hallmark of prion diseases.

Purpose of the Study:

  • To investigate the spontaneous conversion of the Y145Stop PrP variant (huPrP23-144) into amyloid fibrils.
  • To identify the specific region within huPrP23-144 essential for amyloid fibril formation.

Main Methods:

  • Recombinant polypeptide expression and purification of huPrP23-144 and its fragments.
  • Characterization of fibril formation using protein concentration-dependent assays, atomic force microscopy (AFM), and Fourier-transform infrared (FTIR) spectroscopy.
  • Systematic deletion analysis of PrP fragments to pinpoint critical regions for amyloidogenesis.

Main Results:

  • huPrP23-144 spontaneously converts from a disordered monomeric state to amyloid fibrils via nucleation-dependent polymerization.
  • AFM revealed periodicity in fibrils, and FTIR confirmed the formation of beta-sheet structures, distinct from shorter model peptides.
  • Residues 138-141 were identified as essential for huPrP23-144 self-seeded assembly into amyloid fibrils.

Conclusions:

  • The Y145Stop PrP fragment possesses intrinsic properties enabling spontaneous amyloid formation.
  • The 138-141 region of PrP is critical for the conformational conversion and self-assembly into amyloid fibrils associated with this disease mutation.
  • Findings provide insights into the molecular mechanisms underlying prion protein misfolding and aggregation in disease.

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