Building gamma-secretase: the bits and pieces

Area of Science:

• Molecular Biology
• Neuroscience
• Proteolysis

Background:

• Gamma-secretase is a key protease for intramembrane cleavage of type I transmembrane proteins.
• Its substrates are vital for cell fate, adhesion, and neurogenesis.
• Key substrates include amyloid precursor protein and Notch.

Purpose of the Study:

• To elucidate the assembly, stoichiometry, activation, and subcellular localization of the gamma-secretase complex.
• To understand the structural basis for intramembrane proteolysis.

Main Methods:

• 3D-Electron Microscopy (3D-EM) rendering.
• Analysis of protein complex assembly and regulation.

Main Results:

• 3D-EM revealed a translucent inner space within the gamma-secretase complex, suggesting a water-filled cavity for proteolysis.
• Gamma-secretase assembly is tightly regulated by ER-Golgi recycling and occurs in post-Golgi compartments.

Conclusions:

• Understanding gamma-secretase function requires unraveling its complex assembly, activation, and localization.
• The structural insights from 3D-EM are crucial for understanding its intramembrane cleavage mechanism.