Mar 11, 2020

Mechanisms of γ-Secretase Activation and Substrate Processing

bioRxiv
Apurba BhattaraiYinglong Miao

Abstract

Amyloid β-peptide, the principal component of characteristic cerebral plaques of Alzheimer's disease (AD), is produced through intramembrane proteolysis of the amyloid precursor protein (APP) by γ-secretase. Despite the importance in pathogenesis of AD, the mechanisms of intramembrane proteolysis and substrate processing by γ-secretase remain poorly understood. Here, complementary all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method and biochemical experiments were combined to investigate substrate processing of wildtype and mutant APP by γ-secretase. The GaMD simulations captured spontaneous activation of γ-secretase, with hydrogen bonded catalytic aspartates and water poised for proteolysis of APP at the ϵ cleavage site. Furthermore, GaMD simulations revealed that familial AD mutations I45F and T48P enhanced the initial ϵ cleavage between residues Leu49-Val50, while M51F mutation shifted the ϵ cleavage site to the amide bond between Thr48-Leu49. Detailed analysis of the GaMD simulations allowed us to identify distinct low-energy conformational states of γ-secretase, different secondary structures of the wildtype and mutant APP substrate, and important active-site sub-pockets for catalytic ...Continue Reading

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Mentioned in this Paper

Alzheimer's Disease
Amyloid beta-Protein Precursor
Protein Conformation
Analysis
Gaussian Kernel
Mutant
Structure
Simulation
Amyloid beta-Peptides
Plaque (Lesion)

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