Specific Keratinase Derived Designer Peptides Potently Inhibit A β Aggregation Resulting in Reduced Neuronal Toxicity and Apoptosis.

Specific Keratinase Derived Designer Peptides Potently Inhibit A β Aggregation Resulting in Reduced Neuronal Toxicity and Apoptosis. Biochem J. 2019 May 28;: Authors: Rajput R, G L B, Srivastava A, Wahi D, Shrivastava N, Kundu B, Grover A Abstract Compelling evidences implicate self-assembly of amyloid- β (A β 1-42) peptides into soluble oligomers and fibrils as a major underlying event in Alzheimer's disease (AD) pathogenesis. Herein, we employed amyloid-degrading keratinase (kerA) enzyme as a key A β 1-42-binding scaffold to identify five keratinase-guided peptides (KgPs) capable of interacting with and altering amyloidogenic conversion of A β 1-42 The KgPs showed micromolar affinities with A β 1-42 and abolished its sigmoidal amyloidogenic transition, resulting in abrogation of fibrillogenesis. Comprehensive assessment using dynamic light scattering (DLS), atomic force microscopy (AFM) and Fourier-transform infrared (FTIR) spectroscopy showed that KgPs induced formation of off-pathway oligomers comparatively larger than the native A β 1-42 oligomers but with a significantly reduced cross- β signature. These off-pathway oligomers exhibited low immunoreactivity against oligomer-specific (A11) and fibril-specific (OC) antibodies and rescued neuronal cells from A β 1-42 oligomer toxicity as well as neuronal apoptosis. Structural analysis using molecular docking and molecular dynamics (MD) simulations showed two preferred KgP ...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research