The C-terminal threonine of Aβ43 nucleates toxic aggregation via structural and dynamical changes in monomers and protofibrils.
Recent studies suggest that deposition of amyloid β (Aβ) into oligomeric aggregates and fibrils, hallmarks of Alzheimer's disease, may be initiated by the aggregation of Aβ species other than the well-studied 40- and 42-residue forms, Aβ40 and Aβ42, respectively. Here we report on key structural, dynamic, and aggregation kinetic parameters of Aβ43, extended by a single threonine at the C-terminus relative to Aβ42. Using aggregation time course experiments, electron microscopy, and a combination of nuclear magnetic resonance measurements including backbone relaxation, dark-state exchange saturation transfer, and quantification of chemical shift differences and scalar coupling constants, we demonstrate that the C-terminal threonine in Aβ43 increases the rate and extent of protofibril aggregation and confers slow C-terminal motions in the monomeric and protofibril-bound forms of Aβ43. Relative to the neighboring residues, the hydrophilic Thr43 of Aβ43 favors direct contact with the protofibril surface more so than the C-terminus of Aβ40 or Aβ42. Taken together, these results demonstrate the potential of a small chemical modification to affect the properties of Aβ structure and aggregation, providing a mechanism for the potential role of Aβ43 as a primary nucleator of Aβ aggregates in Alzheimer's disease.
Graduate Program in Molecular Biology, Cell Biology, and Biochemistry and ‡Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University , Providence, Rhode Island 02912, United States.
Alexander E
AE
Conicella
Nicolas L
NL
Fawzi
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D013912:Threonine / Q000737:chemistry* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C098994:amyloid beta-protein (1-43); D013912:Threonine