Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15-28 fragment of the Alzheimer amyloid-beta protein.
Amyloid fibrils, large ordered aggregates of amyloid beta proteins (Abeta), are clinical hallmarks of Alzheimer's disease (AD). The aggregation properties of amyloid beta proteins can be strongly affected by single-point mutations at positions 22 and 23. The Dutch mutation involves a substitution at position 22 (E22Q) and leads to increased deposition rates of the AbetaE22Q peptide onto preseeded fibrils. We investigate the effect of the E22Q mutation on two key regions involved in the folding and aggregation of the Abeta peptide through replica exchange molecular dynamics simulations of the 15-28 fragment of the Abeta peptide. The Abeta15-28 peptide encompasses the 22-28 region that constitutes the most structured part of the Abeta peptide (the E22-K28 bend), as well as the central hydrophobic cluster (CHC) (segment 17-21), the primary docking site for Abeta monomers depositing onto fibrils. Our simulations show that the 22-28 bend is preserved in the Abeta(15-28) peptide and that the CHC, which is mostly unstructured, interacts with this bend region. The E22Q mutation does not affect the structure of the bend but weakens the interactions between the CHC and the bend. This leads to an increased population of beta-structure in the CHC. Our analysis of the fibril elongation reaction reveals that the CHC adopts a beta-strand conformation in the transition state ensemble, and that the E22Q mutation increases aggregation rates by lowering the barrier for Abeta monomer deposition onto a fibril. Thermodynamic signatures of this enhanced fibrillization process from our simulations are in good agreement with experimental observations.
Baumketner
Andrij
A
Department of Physics and Optical Science, University of North Carolina, Charlotte, NC 28223, USA. abaumket@uncc.edu
Krone
Mary Griffin
MG
Shea
Joan-Emma
JE
D000544:Alzheimer Disease / Q000235:genetics*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics*; D019277:Entropy; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics; D005973:Glutamine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009426:Netherlands; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding; D044465:White People / Q000235:genetics
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C501831:amyloid beta-protein (21-30); C528685:beta-amyloid (15-28); D005973:Glutamine; D018698:Glutamic Acid