Nicastrin functions as a γ-secretase-substrate receptor

Sanjiv Shah, Sheu Fen Lee, Katsuhiko Tabuchi, Yi Heng Hao, Cong Yu, Quincey LaPlant, Haydn Ball, Charles E. Dann, Thomas Südhof, Gang Yu

Research output: Contribution to journalArticlepeer-review

385 Scopus citations


γ-secretase catalyzes the intramembrane cleavage of amyloid precursor protein (APP) and Notch after their extracellular domains are shed by site-specific proteolysis. Nicastrin is an essential glycoprotein component of the γ-secretase complex but has no known function. We now show that the ectodomain of nicastrin binds the new amino terminus that is generated upon proteolysis of the extracellular APP and Notch domains, thereby recruiting the APP and Notch substrates into the γ-secretase complex. Chemical- or antibody-mediated blocking of the free amino terminus, addition of purified nicastrin ectodomain, or mutations in the ectodomain markedly reduce the binding and cleavage of substrate by γ-secretase. These results indicate that nicastrin is a receptor for the amino-terminal stubs that are generated by ectodomain shedding of type I transmembrane proteins. Our data are consistent with a model where nicastrin presents these substrates to γ-secretase and thereby facilitates their cleavage via intramembrane proteolysis.

Original languageEnglish (US)
Pages (from-to)435-447
Number of pages13
Issue number3
StatePublished - Aug 12 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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