Membrane Dynamics of γ‑Secretase Provides a Molecular Basis for β‑Amyloid Binding and Processing

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
multitemplate 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, semiopen, and closed) that remarkably
differ by tilting of helices 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 semiopen conformation consistently
shows the best fit of Aβ peptides, that is, 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 semiopen “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.