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...  Read more

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 terminus. Interestingly, the signal peptide peptidase (SPP), an intramembrane protease that is most closely related to PS, does not need a cofactor protein for catalytic activity but does require prior substrate shedding, suggesting that recognition/binding of the substrate amino terminus by the γ-secretase complex may be carried out by presenilin, although the participation of Aph1 and/or Pen2 cannot be ruled out.

Additionally, given that the extremely unstable “nicastrin-less” γ-secretase complex maintains approximately 50 percent of the wild-type enzyme activity, this result strongly suggests that nicastrin is not crucial for substrate recognition/binding. Nevertheless, our data and the findings presented in this article cannot exclude another contribution of nicastrin to γ-secretase activity and/or specificity, although no biochemical data have been published to support this assumption.

The model of nicastrin as the substrate receptor for the γ-secretase complex is exclusively supported by the putative interaction between the Glu333 and the N-terminus of the substrate. In contrast, our published data has shown that mutations in the putative binding pocket, including Glu332 (Glu333 in human), affect the levels of the mature γ-secretase complex in the mutant cell lines, but they do not have an effect on the specific activity of the complex. Therefore, our results exclude the participation of the Glu332 in the activity of the complex and indicate that the observed effects could be due to a problem in the assembly or maturation (stability) of the mutant complexes. Importantly, the results presented by Zhao et al. elegantly corroborate our findings and present a “simplified” version of the γ-secretase complex that advances our understanding of its structure-function.

γ-secretase has been considered as a potential drug target for Alzheimer disease. The proposal of nicastrin as a gatekeeper of the enzyme complex presented the opportunity to approach the γ-secretase “drug targetability” from a different angle. However, the fact that two independent studies present data that do not support this model not only reopens the discussion about the function of nicastrin in the γ-secretase complex, but also adds a question mark to this drug-targeting strategy.

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