10.1021/acschembio.9b00309.s001
Eduard V. Bocharov
Eduard V.
Bocharov
Kirill D. Nadezhdin
Kirill D.
Nadezhdin
Anatoly S. Urban
Anatoly S.
Urban
Pavel E. Volynsky
Pavel E.
Volynsky
Konstantin V. Pavlov
Konstantin V.
Pavlov
Roman G. Efremov
Roman G.
Efremov
Alexander S. Arseniev
Alexander S.
Arseniev
Olga V. Bocharova
Olga V.
Bocharova
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
American Chemical Society
2019
amyloid -β.
APP sequential proteolysis
amyloid -β peptides
lipid bilayer
ε- site
APP transmembrane
amyloid -β precursor protein
cleavage
age-related pathology
γ- secretase
Alzheimer
mutations influence production
APP TM domain helix
Alternative APP Transmembrane Domain Cleavage Cascades
molecular-level events
APP TM domain
amyloidogenic peptides
membrane-mimicking micelles
NMR
age-related onset
oxidative stress
Familial L 723P Mutation
L 723P mutation
Straightforward Mechanism
structural-dynamic behavior
mechanism
Local Unfolding
novel treatment strategies
protein backbone
dynamics simulations
2019-06-10 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Familial_L723P_Mutation_Can_Shift_the_Distribution_between_the_Alternative_APP_Transmembrane_Domain_Cleavage_Cascades_by_Local_Unfolding_of_the_Cleavage_Site_Suggesting_a_Straightforward_Mechanism_of_Alzheimer_s_Disease_Pathogenesis/8295194
Alzheimer’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.