Cryo-EM structures of human γ-secretase

gamma-secretase, a membrane-embedded aspartate protease, catalyzes peptide bond hydrolysis of a large variety of type I integral membrane proteins exemplified by amyloid precursor protein (APP). Cleavage of APP leads to formation of beta-amyloid plaque, which is a hallmark of Alzheimer's disease (AD). Over 200 AD-associated mutations are mapped to presenilin 1 (PS1), the catalytic component of gamma-secretase. In the past three years, several cryo-electron microscopy (cryo-EM) structures of human gamma-secretase have been determined at near atomic resolutions. Here we summarize the methods involved and discuss structural features of gamma-secretase and the associated functional insights.