ACS Chem Biol, 2019, 14(7):1573-1582

Familial L723P Mutation Can Shift the Distribution between the Alternative APP Transmembrane Domain Cleavage Cascades by Local Unfolding of the η-Cleavage Site Suggesting a Straightforward Mechanism of Alzheimer's Disease Pathogenesis

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 ?-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.

IBCH: 8037
Ссылка на статью в журнале: http://pubs.acs.org/doi/10.1021/acschembio.9b00309
Кол-во цитирований на 10.2023: 12
Данные статьи проверены модераторами 2019-07-07

Список научных проектов, где отмечена публикация

  1. - (January 6, 2017 — December 31, 2019). Bocharova O.V.. Grant, RFBR.
  2. 18-54-74001. . Сommercial.
  3. CKP IBCH (January 6, 2019 — December 31, 2022). . Сommercial.
  4. -Молекулярно-биофизические аспекты олигомеризации мембранных доменов рецепторов, определяющие клеточную сигнализацию в норме и онкогенезе (January 6, 2018 — December 31, 2022). Efremov R.G.. Grant, RSF.