Recent Advances Unravel γ-Secretase's Substrate Recognition, Drug Sites, and Physiological Roles

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides. These Aβ peptides are generated through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. While γ-secretase is crucial for various physiological processes, its role in AD, specifically in producing aggregation-prone Aβ, makes it a prime therapeutic target. Despite its importance, fundamental questions regarding its substrate recognition, drug-binding sites, and full range of functions have remained largely unanswered, hindering effective drug development.

This review synthesizes recent breakthroughs in structural biology, biochemistry, and computational biology to address the long-standing mysteries surrounding γ-secretase. The authors systematically outline how these advanced methodologies have been applied to elucidate the enzyme's mechanism of action, including how it recognizes and recruits its diverse array of over 150 single-span membrane protein substrates. The paper also explores the identification of drug-binding sites and the comprehensive mapping of its substratome, providing a holistic view of this complex protease.

Recent structural biology advances, particularly cryo-electron microscopy, have provided high-resolution insights into the γ-secretase complex, revealing its unique intramembrane catalytic mechanism. Biochemical studies have clarified how the enzyme binds and unfolds its substrates, demonstrating a dynamic interaction crucial for cleavage. Computational biology, including molecular dynamics simulations, has been instrumental in predicting substrate recognition motifs and identifying potential allosteric drug-binding sites beyond the active site.

The review highlights that the full range of γ-secretase's substrates now exceeds 150 single-span membrane proteins, significantly expanding its known physiological roles beyond APP and Notch processing. This expanded understanding of the substratome and catalytic mechanism is paving the way for the development of more selective γ-secretase modulators, which aim to reduce neurotoxic Aβ production without disrupting other essential γ-secretase functions.