Membrane dynamics of γ-secretase provides a molecular basis for Aβ binding and processing

Arun Kumar Somavarapu, Kasper Planeta Kepp

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Abstract

γ-secretase produces β-amyloid (Aβ) within its presenilin (PS1) subunit, mutations in which cause Alzheimer’s disease, and current therapies thus seek to modulate its activity. While the general structure is known from recent electron microscopy studies, direct loop- and membrane-interactions and explicit dynamics relevant to substrate processing remain unknown. We report a modeled structure utilizing the optimal multi-template information available, including loops and missing side chains, account of maturation cleavage, and explicit all-atom molecular dynamics in the membrane. We observe three distinct conformations of γ-secretase (open, semi-open, and closed) that remarkably differ by tilting of helix 2 and 3 of PS1, directly controlling active site availability. The large hydrophilic loop of PS1 where maturation occurs reveals a new helix segment that parallels the likely helix character of other substrates. The semi-open conformation consistently shows the best fit of Aβ peptides, i.e. longer residence before release and by inference more trimming. In contrast, the closed, hydrophobic conformation is largely inactive and the open conformation is active but provides fewer optimal interactions and induces shorter residence time and by inference releases Aβ peptides of longer lengths. Our simulations thus provide a molecular basis for substrate processing and changes in the Aβ42/Aβ40 ratio. Accordingly, selective binding to protect the semi-open “innocent” conformation provides a molecular recipe for effective γ-secretase modulators; we provide the full atomic structures for these states that may play a key role in developing selective γ-secretase modulators for treatment of Alzheimer’s disease.
Original languageEnglish
JournalACS Chemical Neuroscience
Volume8
Issue number11
Pages (from-to)2424-2436
ISSN1948-7193
DOIs
Publication statusPublished - 2017

Keywords

  • γ-secretase
  • PSEN1
  • Alzheimer’s Disease
  • Conformation change
  • β-amyloid

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