nicastrin

Nicastrin is a type I transmembrane glycoprotein that serves as a core component of the gamma-secretase protease complex. Gamma-secretase is an intramembrane protease that cleaves a range of type I transmembrane substrates, including Notch receptors and the amyloid precursor protein (APP).

In humans, nicastrin is encoded by the NCSTN gene. The protein features a large extracellular domain, a single transmembrane helix, and a short cytoplasmic tail. It is highly glycosylated and resides as part of the assembled gamma-secretase complex, which includes presenilin 1 or 2, APH-1, and PEN-2.

Functionally, nicastrin is thought to act as the substrate receptor of gamma-secretase, recognizing and stabilizing substrates for proteolysis within the membrane. It contributes to complex maturation and substrate selectivity, facilitating the cleavage of Notch and APP to release signaling fragments such as the Notch intracellular domain and amyloid-beta. Proper nicastrin function is required for gamma-secretase activity, although the precise mechanisms of substrate recognition are an active area of study.

Clinical relevance: Mutations in NCSTN have been associated with familial hidradenitis suppurativa, a chronic inflammatory skin disorder. Because gamma-secretase also processes Notch, pharmacological inhibition of the complex can disrupt Notch signaling and cause adverse effects; this has influenced the development of gamma-secretase inhibitors as potential therapeutics for Alzheimer's disease.