Molecular dynamics simulation study reveals potential substrate entry path into γ-secretase/presenilin-1

Area of Science:

• Structural Biology and Biochemistry
• Neuroscience and Molecular Medicine

Background:

• Presenilin 1 (PS1) is the catalytic core of γ-secretase, an enzyme complex involved in cleaving proteins like amyloid precursor protein (APP) and Notch.
• Dysfunctional APP cleavage by γ-secretase is implicated in Alzheimer's disease (AD) pathogenesis, highlighting the need to understand its intramembrane hydrolysis mechanism.
• The precise mechanism of γ-secretase's proteolytic activity within the hydrophobic lipid bilayer remains poorly understood.

Purpose of the Study:

• To elucidate the dynamic behavior and mechanism of human Presenilin 1 (PS1) during intramembrane proteolysis within a lipid bilayer.
• To investigate the role of specific transmembrane domains (TMs) and lipid interactions in modulating γ-secretase activity.
• To identify potential substrate entry pathways for γ-secretase-mediated hydrolysis.

Main Methods:

• Construction of a homology model for human PS1.
• Molecular dynamics (MD) simulations of PS1 within explicit membrane phospholipids.
• Analysis of TM9 flexibility, PALP motif function, and interactions with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE).

Main Results:

• TM9 exhibits significant flexibility, facilitating 'gate-open' movements of TM2 and TM6, thereby exposing catalytic residues (Asp257, Asp385).
• The conserved PALP motif anchors TM6, mediating conformational changes induced by TM9.
• Direct interactions between POPE lipids and the PS1 active site suggest lipids can modulate enzyme activity; intermediate states indicate a substrate pathway via TM2/TM6 interface.

Conclusions:

• This study provides the first molecular simulation insights into the dynamic structure of human PS1 within a lipid bilayer.
• The findings reveal a potential substrate entry mechanism influenced by TM9 dynamics and lipid interactions.
• Understanding these dynamic behaviors and lipid modulations is critical for developing novel therapeutic strategies targeting γ-secretase for Alzheimer's disease.