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Familial L723P Mutation Can Shift the Distribution between the Alternative APP Transmembrane Domain Cleavage Cascades by Local Unfolding of the Ε‑Cleavage Site Suggesting a Straightforward Mechanism of Alzheimer’s Disease Pathogenesis
journal contribution
posted on 2019-06-10, 00:00 authored by Eduard V. Bocharov, Kirill D. Nadezhdin, Anatoly S. Urban, Pavel E. Volynsky, Konstantin V. Pavlov, Roman G. Efremov, Alexander S. Arseniev, Olga V. BocharovaAlzheimer’s
disease is an age-related pathology associated
with accumulation of amyloid-β peptides, products of enzymatic
cleavage of amyloid-β precursor protein (APP) by secretases.
Several familial mutations causing early onset of the disease have
been identified in the APP transmembrane (TM) domain. The mutations
influence production of amyloid-β, but the molecular mechanisms
of this effect are unclear. The “Australian” (L723P)
mutation located in the C-termini of APP TM domain is associated with
autosomal-dominant, early onset Alzheimer’s disease. Herein,
we describe the impact of familial L723P mutation on the structural-dynamic
behavior of APP TM domain studied by high-resolution NMR in membrane-mimicking
micelles and augmented by molecular dynamics simulations in explicit
lipid bilayer. We found L723P mutation to cause local unfolding of
the C-terminal turn of the APP TM domain helix and increase its accessibility
to water required for cleavage of the protein backbone by γ-secretase
in the ε-site, thus switching between alternative (“pathogenic”
and “non-pathogenic”) cleavage cascades. These findings
suggest a straightforward mechanism of the pathogenesis associated
with this mutation, and are of generic import for understanding the
molecular-level events associated with APP sequential proteolysis
resulting in accumulation of the pathogenic forms of amyloid-β.
Moreover, age-related onset of Alzheimer’s disease can be explained
by a similar mechanism, where the effect of mutation is emulated by
the impact of local environmental factors, such as oxidative stress
and/or membrane lipid composition. Knowledge of the mechanisms regulating
generation of amyloidogenic peptides of different lengths is essential
for development of novel treatment strategies of the Alzheimer’s
disease.
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Keywords
amyloid -β.APP sequential proteolysisamyloid -β peptideslipid bilayerε- siteAPP transmembraneamyloid -β precursor proteincleavageage-related pathologyγ- secretaseAlzheimermutations influence productionAPP TM domain helixAlternative APP Transmembrane Domain Cleavage Cascadesmolecular-level eventsAPP TM domainamyloidogenic peptidesmembrane-mimicking micellesNMRage-related onsetoxidative stressFamilial L 723P MutationL 723P mutationStraightforward Mechanismstructural-dynamic behaviormechanismLocal Unfoldingnovel treatment strategiesprotein backbonedynamics simulations
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