Structural biology of intramembrane proteases: mechanistic insights from rhomboid and S2P to γ-secretase

Intramembrane proteases catalyze hydrolysis of peptide bond within the lipid bilayer and play a key role in a variety of cellular processes. These membrane-embedded enzymes comprise four major classes: rhomboid serine proteases, site-2 metalloproteases, Rce1-type glutamyl proteases, and aspartyl proteases exemplified by signal peptide peptidase and gamma-secretase. In the past several years, three-dimensional structures of representative members of these four classes of intramembrane protease have been reported at atomic resolutions, which reveal distinct protein folds and active site configurations. These structures, together with structure guided biochemical analyses, shed light on the working mechanisms of water access and substrate entry. In this review, we discuss the shared as well as unique features of these intramembrane proteases, with a focus on presenilin the catalytic component of gamma-secretase.