Initial Substrate Binding of γ‑Secretase:
The Role of Substrate Flexibility
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Abstract
γ-Secretase
cleaves transmembrane domains (TMD) of amyloid precursor protein (APP),
producing pathologically relevant amyloid-β proteins. Initial
substrate binding represents a key step of the γ-secretase cleavage
whose mechanism remains elusive. Through long time scale coarse-grained
and atomic simulations, we have found that the APP TMD can bind to
the catalytic subunit presenilin 1 (PS1) on an extended surface covering
PS1’s TMD2/6/9 and PAL motif that are all known to be essential
for enzymatic activity. This initial substrate binding could lead
to reduction in the vertical gap between APP’s ε-cleavage
sites and γ-secretase’s active center, enhanced flexibility
and hydration levels around the ε-sites, and the presentation
of these sites to the enzyme. There are heterogeneous substrate binding
poses in which the substrate is found to bind to either the N- or
C-terminal parts of PS1, or both. Moreover, we also find that the
stability of the binding poses can be modulated by the flexibility
of substrate TMD. Especially, the APP substrate, when deprived of
bending fluctuation, does not bind to TMD9 at PS1’s C-terminus.
Our simulations have revealed further that another substrate of γ-secretase,
namely, notch receptors, though bearing a rigid TMD, can still bind
to PS1 TMD9, but by a different mechanism, suggesting that the influence
of substrate flexibility is context-dependent. Together, these findings
shed light on the mechanism of initial substrate docking of γ-secretase
and the role of substrate flexibility in this process