Peptide conformation and supramolecular organization in amylin fibrils: constraints from solid-state NMR

Biochemistry. 2007 Nov 27;46(47):13505-22. doi: 10.1021/bi701427q. Epub 2007 Nov 3.

Abstract

The 37-residue amylin peptide, also known as islet amyloid polypeptide, forms fibrils that are the main peptide or protein component of amyloid that develops in the pancreas of type 2 diabetes patients. Amylin also readily forms amyloid fibrils in vitro that are highly polymorphic under typical experimental conditions. We describe a protocol for the preparation of synthetic amylin fibrils that exhibit a single predominant morphology, which we call a striated ribbon, in electron microscopy and atomic force microscopy images. Solid-state nuclear magnetic resonance (NMR) measurements on a series of isotopically labeled samples indicate a single molecular structure within the striated ribbons. We use scanning transmission electron microscopy and several types of one- and two-dimensional solid-state NMR techniques to obtain constraints on the peptide conformation and supramolecular structure in these amylin fibrils and to derive molecular structural models that are consistent with the experimental data. The basic structural unit in amylin striated ribbons, which we call the protofilament, contains four layers of parallel beta-sheets, formed by two symmetric layers of amylin molecules. The molecular structure of amylin protofilaments in striated ribbons closely resembles the protofilament in amyloid fibrils with a similar morphology formed by the 40-residue beta-amyloid peptide that is associated with Alzheimer's disease.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemical synthesis
  • Amyloid / chemistry*
  • Amyloid / ultrastructure
  • Amyloid beta-Peptides / chemistry
  • Animals
  • Humans
  • Islet Amyloid Polypeptide
  • Microscopy, Atomic Force
  • Microscopy, Electron, Scanning Transmission
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptide Fragments / chemistry
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Protein Structure, Secondary
  • Structure-Activity Relationship

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Islet Amyloid Polypeptide
  • Peptide Fragments
  • Peptides
  • amyloid beta-protein (1-40)