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Amyloid and the Cross-Beta Architecture
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Stereospecific amyloid-like fibril formation by a peptide fragment of beta2-microglobulin

Hiromasa Wadai1, Kei-ichi Yamaguchi, Satoshi Takahashi

  • 1Institute for Protein Research, Osaka University, and CREST, Japan Science and Technology Agency, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan.

Biochemistry
|January 5, 2005
PubMed

Insights

Stereospecificity of amino acids influences amyloid fibril formation. L- and D-amino acid peptides form distinct amyloid fibrils, with homologous extension preventing cross-reactivity and maintaining structural integrity.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Materials Science

Background:

  • Amyloid fibrils are implicated in diseases like dialysis-related amyloidosis.
  • Beta(2)-microglobulin is a key component of these amyloid deposits.
  • Understanding amino acid stereospecificity is crucial for elucidating fibril formation mechanisms.

Purpose of the Study:

  • To investigate the role of L/D-amino acid stereospecificity in amyloid fibril formation.
  • To compare the fibril-forming properties of L- and D-enantiomers of a beta(2)-microglobulin peptide.
  • To examine potential cross-reactivity between L- and D-amino acid amyloid fibrils.

Main Methods:

  • Synthesis and characterization of L- and D-amino acid peptides (K3 peptide) from beta(2)-microglobulin.
  • Amyloid fibril formation induced by 2,2,2-trifluoroethanol and HCl.
  • Analysis of fibril formation using thioflavin T fluorescence, circular dichroism, and atomic force microscopy.
  • Seeding experiments to assess monomer extension on preformed seeds.

Main Results:

  • Both L-K3 and D-K3 peptides formed amyloid-like fibrils with opposite chirality.
  • Seeding experiments demonstrated homologous extension: L-monomers extended L-seeds, and D-monomers extended D-seeds.
  • Cross-reaction between L- and D-enantiomers was prevented, suggesting steric hindrance or unfavorable geometry in mixed structures.

Conclusions:

  • Amyloid fibril formation from L- and D-peptides occurs via similar mechanisms but results in stereochemically distinct structures.
  • The observed lack of cross-reactivity is attributed to the inability of mixed beta-sheets to satisfy stabilization factors.
  • Stereospecificity is a critical determinant in the self-assembly of amyloid fibrils, preventing heterotypic interactions.

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