Probing γ-secretase-substrate interactions at the single amino acid residue level.

Intramembrane proteolysis by γ-secretases plays major roles in disease pathology and cellular signalling, yet the dynamics of these enzyme complexes and how they recognize substrates remains poorly understood. New work in The EMBO Journal utilizes photoaffinity crosslinking to map APP interactions to different γ-secretase subunits, suggesting a succession of recruitment and engagement steps that lead up to substrate cleavage.