Ion Mobility-Mass Spectrometry Reveals a Dipeptide That Acts as a Molecular Chaperone for Amyloid ?.

ABSTRACT: Previously, we discovered and structurally characterized a complex between amyloid ? 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 ? 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 ? in order to structurally characterize the complexes formed. We find that FL binds preferentially to amyloid ? oligomers and attaches to amyloid ? 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.

SUBMITTER: Soper-Hopper MT 

PROVIDER: S-EPMC5724361 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature