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 photo‐affinity cross‐linking to map APP interactions to different γ‐secretase subunits, suggesting a succession of recruitment and engagement steps that lead up to substrate cleavage.
See also: A Fukumori & H Steiner (August 2016)
γ‐secretases are fascinating multimeric intramembrane protease complexes involved in a wide spectrum of biological activities (Jurisch‐Yaksi et al, 2013). They cleave many and very different substrates in the membrane using an intriguing multiple turnover mechanism, which releases proteolytic fragments at both sides of the cell membrane and possibly also hydrophobic peptides into the membrane. Many of this newly generated intracellular fragments exert (or are supposed to exert) signalling functions (Jurisch‐Yaksi et al, 2013), while some of the extracellular fragments, like the Aβ fragment generated from the Alzheimer's disease‐related amyloid precursor protein (APP), play a central role in disease pathology (De Strooper & Chávez Gutiérrez, 2015). γ‐secretase complexes consist of presenilin (PSEN), nicastrin (NCT), presenilin enhancer 2 (PEN2) and anterior pharynx defective 1 (APH1) subunits, and perform endoproteolytic, carboxypeptidase‐like, and even aminopeptidase activities (De Strooper & Chávez Gutiérrez, 2015). Details of the interaction of these different subunits have recently been revealed in atomic structures obtained by cryo‐electron microscopy (Bai et al, 2015a,b). However, to unravel crucial questions such as the mechanisms that underlie the different proteolytic activities, the dynamics of the complexes or the way substrates are recognized, further work is needed.
While their relaxed specificity would suggest that γ‐secretase complexes indiscriminately cut type I …
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