Model of Alzheimer's disease amyloid-beta peptide based on a RNA binding protein

Biochem Biophys Res Commun. 2005 Jul 1;332(2):585-92. doi: 10.1016/j.bbrc.2005.04.164.

Abstract

Although Alzheimer's Abeta peptide has been shown to form beta-sheet structure, a high-resolution molecular structure is still unavailable to date. A search for a sequence neighbor using Abeta(10-42) as the query in the Protein Data-Bank (PDB) revealed that an RNA binding protein, AF-Sm1 from Archaeoglobus fulgidus (PDB entry: 1i4k chain Z), shared 36% identical residues. Using AF-Sm1 as a template, we built a molecular model of Abeta(10-42) by applying comparative modeling methods. The model of Abeta(10-42) contains an antiparallel beta-sheet formed by residues 16-23 and 32-41. Hydrophobic surface constituted by residues 17-20 (LVFF) separates distinctly charged regions. Residues that interact with RNA in the AF-Sm1 crystal structure were found to be conserved in Abeta. Using a native gel we demonstrate for the first time that RNA can interact with Abeta and selectively retard the formation of fibrils or higher-order oligomers. We hypothesize that in a similar fashion to AF-Sm1, RNA interacts with Abeta in the beta-hairpin (beta-turn-beta) structure and prevents fibril formation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / analysis
  • Amyloid beta-Peptides / chemistry*
  • Archaeal Proteins / analysis
  • Archaeal Proteins / chemistry*
  • Binding Sites
  • Computer Simulation
  • Dimerization
  • Models, Chemical*
  • Models, Molecular*
  • Molecular Sequence Data
  • Multiprotein Complexes / analysis
  • Multiprotein Complexes / chemistry
  • Protein Binding
  • Protein Conformation
  • RNA-Binding Proteins / analysis
  • RNA-Binding Proteins / chemistry
  • Ribonucleoproteins, Small Nuclear / analysis
  • Ribonucleoproteins, Small Nuclear / chemistry*
  • Sequence Analysis, Protein
  • Sequence Homology, Amino Acid

Substances

  • Amyloid beta-Peptides
  • Archaeal Proteins
  • Multiprotein Complexes
  • RNA-Binding Proteins
  • Ribonucleoproteins, Small Nuclear
  • Sm1 protein, Archaeoglobus fulgidus