title: Ion Mobility-Mass Spectrometry Reveals a Dipeptide That Acts as a Molecular Chaperone for Amyloid β.
abstract: Previously, we discovered and structurally characterized a complex between amyloid β 1-40 and the neuropeptide leucine enkephalin. This work identified leucine enkephalin as a potentially useful starting point for the discovery of peptide-related biotherapeutics for Alzheimer's disease. In order to better understand such complexes that are formed in vitro, we describe here the analysis of a series of site-directed amino acid substitution variants of both peptides, covering the leucine enkephalin sequence in its entirety and a large number of selected residues of amyloid β 1-40 (residues: D1, E3, F4, R5, H6, Y10, E11, H13, H14, Q15, K16, E22, K28, and V40). Ion mobility-mass spectrometry measurements and molecular dynamics simulations reveal that the hydrophobic C-terminus of leucine enkephalin (Phe-Leu, FL) is crucial for the formation of peptide complexes. As such, we explore here the interaction of the dipeptide FL with both wildtype and variant forms of amyloid β in order to structurally characterize the complexes formed. We find that FL binds preferentially to amyloid β oligomers and attaches to amyloid β within the region between its N-terminus and its hydrophobic core, most specifically at residues Y10 and Q15. We further show that FL is able to prevent fibril formation.
authors.affiliation: Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Molly T
authors.initials: MT
authors.lastname: Soper-Hopper
authors.affiliation: Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Eschweiler
authors.affiliation: Department of Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Brandon T
authors.identifier: 0000-0002-6084-2328
authors.initials: BT
authors.lastname: Ruotolo
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016000:Cluster Analysis; D004151:Dipeptides / Q000737:chemistry*; D013058:Mass Spectrometry / Q000379:methods*; D046529:Microscopy, Electron, Transmission; D018832:Molecular Chaperones / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D004151:Dipeptides; D018832:Molecular Chaperones; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)