Abeta42 is more rigid than Abeta40 at the C terminus: implications for Abeta aggregation and toxicity.
Abeta40 and Abeta42 are the major forms of amyloid beta peptides (Abeta) in the brain. Although Abeta42 differs from Abeta40 by only two residues, Abeta42 is much more prone to aggregation and more toxic to neurons than Abeta40. To probe whether dynamics contribute to such dramatic difference in function, backbone ps-ns dynamics of native Abeta monomers were characterized by 15N spin relaxation at 273.3 K and 800 MHz. Abeta42 aggregates much faster than Abeta40 in the NMR tube. The effect of Abeta aggregation was removed from the relaxation measurement by interleaved data collection. R1, R2 and nuclear Overhauser enhancement (NOE) values are similar in Abeta40 and Abeta42, except at the C terminus, indicating Abeta42 and Abeta40 monomers have identical global motions. Comparisons of the spectral density function J(0.87omegaH) and order parameters (S2) indicate that the Abeta42 C terminus is more rigid than the Abeta40 C terminus. At 280.4 K and 287.6 K, the Abeta42 C terminus remains more rigid than the Abeta40 C terminus, suggesting such a dynamical difference is likely present at the physiological temperature. The Abeta42 monomer likely has less configurational entropy due to restricted motion in the C terminus and may pay a smaller entropic price to form fibrils than the Abeta40 monomer. We hypothesize that the entropic difference between Abeta40 and Abeta42 monomers might partly account for the fact that Abeta42 is the major Abeta species in parenchymal senile plaques in most Alzheimer's diseased brains in spite of the predominance of Abeta40 in plasma. The increased rigidity of the Abeta42 C terminus is likely due to its pre-ordering for beta-conformation present in soluble oligomers and fibrils. The Abeta42 C terminus may therefore serve as an internal seed for aggregation.
Yan
Yilin
Y
Biology Department, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Wang
Chunyu
C
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)