Model of Alzheimer’s disease amyloid-β peptide based on a RNA binding protein

Abstract

Although Alzheimer’s Aβ peptide has been shown to form β-sheet structure, a high-resolution molecular structure is still unavailable to date. A search for a sequence neighbor using Aβ 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 Aβ 10–42 by applying comparative modeling methods. The model of Aβ 10–42 contains an antiparallel β-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 Aβ. Using a native gel we demonstrate for the first time that RNA can interact with Aβ and selectively retard the formation of fibrils or higher-order oligomers. We hypothesize that in a similar fashion to AF-Sm1, RNA interacts with Aβ in the β-hairpin (β-turn-β) structure and prevents fibril formation.