An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Amyloid precursor protein (APP) processing by γ-secretase generates amyloid β (Aβ) peptides.
• Specific Aβ lengths are linked to neurotoxic plaque formation in Alzheimer's disease.

Purpose of the Study:

• Investigate the enzyme-substrate interactions of γ-secretase during APP processing.
• Elucidate the structural basis for Aβ peptide length determination.

Main Methods:

• Utilized molecular dynamics simulations based on the APP substrate-bound γ-secretase structure.
• Generated and analyzed model structures of sequentially cleaved APP intermediates.

Main Results:

• Identified a novel internal docking site on γ-secretase with strong enzyme-substrate packing interactions.
• Demonstrated that substrate side chain size and properties at this site influence cleavage patterns and Aβ fragment length.
• Explained how specific mutations (G33I, K28A) alter Aβ production and substrate binding.

Conclusions:

• The internal docking site plays a critical role in regulating sequential APP cleavage by γ-secretase.
• This site's characteristics dictate the length of generated Aβ peptides, impacting Alzheimer's disease pathology.
• The findings offer a structural basis for designing targeted γ-secretase modulators.