Structural basis of human γ-secretase assembly

Area of Science:

• Molecular Biology
• Structural Biology
• Neuroscience

Background:

• The intramembrane protease gamma-secretase (γ-secretase) is implicated in Alzheimer's disease pathogenesis.
• Understanding the precise arrangement of its transmembrane segments (TMs) is crucial for elucidating its function.

Purpose of the Study:

• To determine the 3D structure of human γ-secretase at high resolution.
• To assign the specific transmembrane segments to the four core components of the enzyme.
• To reveal the principles of subunit assembly and the spatial organization of the active site.

Main Methods:

• Single-particle electron cryomicroscopy (cryo-EM) was used to determine the structure.
• The enzyme was purified in the presence of digitonin, with a T4 lysozyme fusion tag on presenilin 1 (PS1).

Main Results:

• A 3D structure of human γ-secretase was resolved at 4.32-Å resolution.
• All 20 transmembrane segments were unambiguously assigned to the four components: PS1, nicastrin, Aph-1, and Pen-2.
• Presenilin 1 (PS1) is centrally located, with its fragments interacting with other subunits.
• Nicastrin's TM associates with Aph-1, and its extracellular domain interacts with Pen-2.
• The catalytic aspartates in PS1 TM6 and TM7 are positioned on the convex side of the transmembrane domain.

Conclusions:

• The determined structure provides a detailed framework for understanding γ-secretase assembly and function.
• This structural insight is vital for future research into Alzheimer's disease mechanisms and therapeutic strategies targeting γ-secretase.