Nicastrin guards Alzheimer's gate.

Alzheimer’s disease is characterized by protein deposits of amyloid-β as plaques in the brain (1). The suite of enzymes that produce amyloid-β by cutting it out of the amyloid-β precursor protein (APP) have long been considered to be prime targets for therapeutic intervention. Converting this promise into reality, however, continues to be stalled by a series of obstacles, including an inaccurate and incomplete understanding of the underlying enzyme mechanisms (2). This challenge has been especially daunting for the multisubunit γ-secretase enzyme that lies embedded in the cell membrane, and ultimately delivers the final intramembrane cut that liberates amyloid-β. In PNAS, Bolduc et al. (3) have now added an unexpected new piece to the γ-secretase puzzle: Nicastrin, the largest component of the γ-secretase complex, functions as a “gatekeeper” that physically blocks large proteins from entering the enzyme’s catalytic center and being cut inappropriately. Background γ-Secretase was originally defined by its role in APP processing, but deeper study revealed it to be an enzymatic “hub” that processes scores of different cell surface proteins (4, 5). The most consequential is the Notch receptor: The effect of blocking γ-secretase activity is accounted for by genetic KO of Notch signaling alone (6). In fact, cleavage of Notch by γ-secretase is itself the trigger that completes a communication circuit between cells that is important during embryonic development and in rapidly renewing adult tissues. Specificity of this communication cascade, therefore, absolutely relies on γ-secretase reliably distinguishing activated from resting Notch receptors. The medical repercussions of this deceptively simple choice loom large: Loss of Notch cleavage is incompatible with life, whereas excess cleavage is implicated in cancer (7). Ultimately, ligand binding to the Notch receptor leads to a series of rearrangements that result in cutting away of the extracellular portion (“ectodomain”) of Notch (8, 9). The short extracellular stub, transmembrane segment, and cytoplasmic signaling domain remain at the membrane and become a substrate for γ-secretase (6). In fact, APP, Notch, and dozens of other γ-secretase substrates share no apparent sequence identity, but all require this “priming” ectodomain shedding to convert them into γ-secretase substrates (10). A lingering question has been precisely how γ-secretase keeps from cleaving full-length substrates when the sequence surrounding the cleavage of both “primed” and resting proteins is identical. One enticing model sprouted from an apparent motif hidden within one of the four essential γ-secretase subunits. Nicastrin, the only subunit with a large ectodomain, itself contains a short sequence that distantly resembles aminopeptidases, or enzymes that evolved to bind amino termini. Early evidence clearly supported this view (11), and nicastrin is now widely considered to be a substrate receptor that binds the new amino terminus as a prerequisite for efficient substrate processing by γ-secretase. Quantitative data to detail the mechanism underlying this attractive Fig. 1. Nicastrin (red) physically blocks large substrates (APP in green) from entering the γ-secretase active site (dark blue) until their ectodomains are removed. Illustration uses coordinates 5A63 (γ-secretase, left complex), 4PWQ (APP E1), 3UMH (APP E2), 2LP1 (APP TM). The three APP domains are separate structures that would be connected through linkers that are not illustrated.