Zhao et al. present a novel and interesting set of findings that shed light on one of the most intriguing features of the γ-secretase enzyme: its dependence on the formation of a high-molecular-weight complex.
This study provides further support for the involvement of nicastrin in assembly, maturation, and stabilization of the γ-secretase complex rather than in substrate recognition or as a crucial component for catalytic activity of the complex. The results presented in this article are in accordance with our previously published study (Chavez-Gutierrez et al., 2008
) and our current working hypothesis for γ-secretase.
Remarkably, this report shows that a nicastrin-less γ-secretase complex, consisting of PS1/APH1a/PEN2, displays indistinguishable catalytic properties relative to the mature γ-secretase (containing nicastrin). Moreover, this nicastrin-less complex also requires ectodomain shedding of the substrate prior to catalysis, demonstrating that nicastrin does not participate in the recognition of the short substrate amino...