title: An early folding contact between Phe19 and Leu34 is critical for amyloid-β oligomer toxicity.
abstract: Small hydrophobic oligomers of aggregation-prone proteins are thought to be generically toxic. Here we examine this view by perturbing an early folding contact between Phe19 and Leu34 formed during the aggregation of Alzheimer's amyloid-β (Aβ40) peptide. We find that even conservative single mutations altering this interaction can abolish Aβ40 toxicity. Significantly, the mutants are not distinguishable either by the oligomers size or by the end-state fibrillar structure from the wild type Aβ40. We trace the change in their toxicity to a drastic lowering of membrane affinity. Therefore, nonlocal folding contacts play a key role in steering the oligomeric intermediates through specific conformations with very different properties and toxicity levels. Our results suggest that engineering the folding energy landscape may provide an alternative route to Alzheimer therapeutics.
authors.affiliation: †Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Anand K
authors.initials: AK
authors.lastname: Das
authors.affiliation: †Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Anoop
authors.initials: A
authors.lastname: Rawat
authors.affiliation: †Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Debanjan
authors.initials: D
authors.lastname: Bhowmik
authors.affiliation: †Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Rucha
authors.initials: R
authors.lastname: Pandit
authors.affiliation: ‡Institute of Medical Physics and Biophysics, University of Leipzig, Härtelstr. 16-18, D-04107 Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huster
authors.affiliation: †Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Maiti
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics* / Q000633:toxicity; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology; D008567:Membranes, Artificial; D009154:Mutation; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics* / Q000633:toxicity; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D017510:Protein Folding; D017208:Rats, Wistar; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D008567:Membranes, Artificial; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D053835:Unilamellar Liposomes; C078592:amyloid beta-protein (1-40); C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Alzheimer therapeutics; Protein aggregation; folding landscape; membrane affinity; neurodegeneration; small oligomers