Structures of beta-amyloid peptide 1-40, 1-42, and 1-55-the 672-726 fragment of APP-in a membrane environment with implications for interactions with gamma-secretase.
Aggregation of Amyloid beta (Abeta) peptide has been linked to the neurodegenerative Alzheimer's Disease and implicated in other amyloid diseases including cerebral amyloid angiopathy. Abeta peptide is generated by cleavage of the amyloid precursor protein (APP) by transmembrane proteases. It is crucial to determine the structures of beta-amyloid peptides in a membrane to provide a molecular basis for the cleavage mechanism. We report the structures of amyloid beta peptide (Abeta(1-40) and Abeta(1-42)) as well as the 672-726 fragment of APP (referred to as Abeta(1-55)) in a membrane environment determined by replica-exchange molecular dynamics simulation. Abeta(1-40) is found to have two helical domains A (13-22) and B(30-35) and a type I beta-turn at 23-27. The peptide is localized at the interface between membrane and solvent. Substantial fluctuations in domain A are observed. The dominant simulated tertiary structure of Abeta(1-40) is observed to be similar to the simulated Abeta(1-42) structure. However, there are differences observed in the overall conformational ensemble, as characterized by the two-dimensional free energy surfaces. The fragment of APP (Abeta(1-55)) is observed to have a long transmembrane helix. The position of the transmembrane region and ensemble of membrane structures are elucidated. The conformational transition between the transmembrane Abeta(1-55) structure, prior to cleavage, and the Abeta(1-40) structure, following cleavage, is proposed.
Miyashita
Naoyuki
N
Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA.
Straub
John E
JE
Thirumalai
D
D
D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D008567:Membranes, Artificial; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D008567:Membranes, Artificial; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases