From mechanism to substratome: Unraveling mysteries of γ-secretase.

γ-Secretase is a pivotal membrane-embedded protease that cleaves more than 150 single-span membrane proteins within their transmembrane domains. While γ-secretase is involved in a wide range of physiological processes, it is best known for its critical role in Alzheimer's disease, where it cleaves a C-terminal fragment of the amyloid precursor protein into small aggregation-prone and neurotoxic peptides. However, how γ-secretase recognizes and recruits its substrates, how it binds and unfolds them, where drug-binding sites are located, and what the full range of its substrates and functions is, have all remained unknown. These long-standing questions have been at the forefront of research for the past decade and are now increasingly being solved. In this review, we outline how recent advances in structural biology, biochemistry, and computational biology have helped to elucidate these mysteries. We also highlight future research directions needed to achieve a comprehensive understanding of this fascinating enzyme, a major therapeutic target for which Alzheimer's disease drugs are now on the horizon.