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
| Autor: | Roman G. Efremov, Anatoly S. Urban, Kirill D. Nadezhdin, Konstantin V. Pavlov, Alexander S. Arseniev, Pavel E. Volynsky, Eduard V. Bocharov, Olga V. Bocharova |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Lipid Bilayers Molecular Dynamics Simulation Disease pathogenesis Cleavage (embryo) 01 natural sciences Biochemistry Amyloid beta-Protein Precursor 03 medical and health sciences Protein Domains Alzheimer Disease mental disorders Humans Point Mutation Amino Acid Sequence Protein Unfolding chemistry.chemical_classification biology 010405 organic chemistry General Medicine 0104 chemical sciences Cell biology Transmembrane domain 030104 developmental biology Enzyme chemistry Proteolysis biology.protein Molecular Medicine Amyloid precursor protein secretase |
| Zdroj: | ACS Chemical Biology. 14:1573-1582 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.9b00309 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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