We read with great interest the manuscript of Zhang et al. They provide preliminary evidence for a predicted novel peptide-binding region in the ectodomain of nicastrin (Nct), which could have a potential role in substrate recruitment to the γ-secretase complex.
We would like to comment on a few specific points in the manuscript:
1. While the inhibitory effect of the anti-Nct antibody and the mutagenesis data provide evidence for the involvement of Nct ectodomain in γ-secretase activity and suggest a possible role for Nct in substrate recruitment, alternative interpretations, such as steric hindrance caused by the binding of the antibody or effects on the overall conformation of the complex, are also possible, and have not been excluded or discussed in this study. As the authors point out, it is likely that only crystallization studies will provide a definitive answer to this question, and, in fact, we completely agree with this conclusion.
2. In our previous study, we proposed that the nicastrin ectodomain was necessary for maturation of γ-secretase, but not for...