title: Rationally designed turn promoting mutation in the amyloid-β peptide sequence stabilizes oligomers in solution.
abstract: Enhanced production of a 42-residue beta amyloid peptide (Aβ(42)) in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD). The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs) in the brain of AD patients. Despite being significant to the understanding of AD mechanism, no atomic-resolution structures are available for these species due to the evanescent nature of ADDLs that hinders most structural biophysical investigations. Based on our molecular modeling and computational studies, we have designed Met35Nle and G37p mutations in the Aβ(42) peptide (Aβ(42)Nle35p37) that appear to organize Aβ(42) into stable oligomers. 2D NMR on the Aβ(42)Nle35p37 peptide revealed the occurrence of two β-turns in the V24-N27 and V36-V39 stretches that could be the possible cause for the oligomer stability. We did not observe corresponding NOEs for the V24-N27 turn in the Aβ(21-43)Nle35p37 fragment suggesting the need for the longer length amyloid peptide to form the stable oligomer promoting conformation. Because of the presence of two turns in the mutant peptide which were absent in solid state NMR structures for the fibrils, we propose, fibril formation might be hindered. The biophysical information obtained in this work could aid in the development of structural models for toxic oligomer formation that could facilitate the development of therapeutic approaches to AD.
authors.affiliation: Biomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, California, United States of America.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.forename: Corey W
authors.initials: CW
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Novick
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Kelley
authors.forename: Mohammed
authors.initials: M
authors.lastname: Inayathullah
authors.forename: Melburne C
authors.initials: MC
authors.lastname: Lemieux
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D004058:Diffusion; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015202:Protein Engineering / Q000379:methods*; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D012996:Solutions
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D050505:Mutant Proteins; D010446:Peptide Fragments; D012996:Solutions; C075222:amyloid beta-protein (1-42)