Membrane dynamics of γ-secretase with the anterior pharynx-defective 1B subunit.
APH1-B
Alzheimer's disease
membrane protein
molecular dynamics
γ-secretase
Journal
Journal of cellular biochemistry
ISSN: 1097-4644
Titre abrégé: J Cell Biochem
Pays: United States
ID NLM: 8205768
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
31
03
2020
accepted:
13
07
2020
pubmed:
25
8
2020
medline:
28
7
2021
entrez:
25
8
2020
Statut:
ppublish
Résumé
The four-subunit protease complex γ-secretase cleaves many single-pass transmembrane (TM) substrates, including Notch and β-amyloid precursor protein to generate amyloid-β (Aβ), central to Alzheimer's disease. Two of the subunits anterior pharynx-defective 1 (APH-1) and presenilin (PS) exist in two homologous forms APH1-A and APH1-B, and PS1 and PS2. The consequences of these variations are poorly understood and could affect Aβ production and γ-secretase medicine. Here, we developed the first complete structural model of the APH-1B subunit using the published cryo-electron microscopy (cryo-EM) structures of APH1-A (Protein Data Bank: 5FN2, 5A63, and 6IYC). We then performed all-atom molecular dynamics simulations at 303 K in a realistic bilayer system to understand both APH-1B alone and in γ-secretase without and with substrate C83-bound. We show that APH-1B adopts a 7TM topology with a water channel topology similar to APH-1A. We demonstrate direct transport of water through this channel, mainly via Glu84, Arg87, His170, and His196. The apo and holo states closely resemble the experimental cryo-EM structures with APH-1A, however with subtle differences: The substrate-bound APH-1B γ-secretase was quite stable, but some TM helices of PS1 and APH-1B rearranged in the membrane consistent with the disorder seen in the cryo-EM data. This produces different accessibility of water molecules for the catalytic aspartates of PS1, critical for Aβ production. In particular, we find that the typical distance between the catalytic aspartates of PS1 and the C83 cleavage sites are shorter in APH-1B, that is, it represents a more closed state, due to interactions with the C-terminal fragment of PS1. Our structural-dynamic model of APH-1B alone and in γ-secretase suggests generally similar topology but some notable differences in water accessibility which may be relevant to the protein's existence in two forms and their specific function and location.
Substances chimiques
Membrane Proteins
0
APH1B protein, human
EC 3.4.-
Amyloid Precursor Protein Secretases
EC 3.4.-
Endopeptidases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
69-85Informations de copyright
© 2020 Wiley Periodicals LLC.
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