Structures of oligomers of a peptide from β-amyloid

J Am Chem Soc. 2013 Aug 21;135(33):12460-7. doi: 10.1021/ja4068854. Epub 2013 Aug 8.

Abstract

Amyloid oligomers play a central role in Alzheimer's and other amyloid diseases, and yet the structures of these heterogeneous and unstable species are not well understood. To better understand the structures of oligomers formed by amyloid-β peptide (Aβ), we have incorporated a key amyloidogenic region of Aβ into a macrocyclic peptide that stabilizes oligomers and facilitates structural elucidation by X-ray crystallography. This paper reports the crystallographic structures of oligomers and oligomer assemblies formed by a macrocycle containing the Aβ(15-23) nonapeptide. The macrocycle forms hydrogen-bonded β-sheets that assemble into cruciform tetramers consisting of eight β-strands in a two-layered assembly. Three of the cruciform tetramers assemble into a triangular dodecamer. These oligomers further assemble in the lattice to form hexagonal pores. Molecular modeling studies suggest that the natural Aβ peptide can form similar oligomers and oligomer assemblies. The crystallographic and molecular modeling studies suggest the potential for interaction of the oligomers with cell membranes and provide insights into the role of oligomers in amyloid diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Crystallography, X-Ray
  • Models, Molecular
  • Protein Multimerization*
  • Protein Structure, Secondary

Substances

  • Amyloid beta-Peptides

Associated data

  • PDB/4IVH