This is a very daring structural proposal, which will stimulate and spark many discussions. The monomeric rhodopsin structure imposes significant problems for the homology modelling of dimeric GPCRs. Here it is employed for the structure prediction of a far more complex system involving additional TM domains and many protein protein interactions. The supporting movie displays a very appealing pore, but the substrate must enter from the side. Furthermore, this pore must be regulated or blocked under normal conditions, otherwise it would be an unregulated aqueaporin with a giant opening. Further structures based on Asp KOs may be "caught in the act" with the substrate.

View all comments by Boris Schmidt

The main finding of this study is that using NMR studies in SDS micelles, the authors determined the structure of PS1 CTF. The structure fits well with previous studies using cysteine accessibility methods by us and by Bart de Strooper’s group. This is important because it is a first structure of a part of PS1 resolved at the atomic level. The study’s potential impact could come from an intriguing feature it shows around catalytic aspartate residue 385, that is, a half helix and extended structure kinked by a glycine residue located near the aspartate. This supports the notion that intramembrane cleavage is occurring within the water-accessible pore structure in the membrane.

At the same time, further study (e.g., using holoprotein) is required, as the PS1 N-terminal fragment (NTF) is also required for the proteolytic activity. Moreover, we have identified that TMD1 of PS1 also faces the catalytic pore (Takagi et al., unpublished result), suggesting that several TMDs in NTFs are involved in the formation of the catalytic pore.

Without an atomic structure, it is impossible...  Read more

The main finding of this study is that using NMR studies in SDS micelles, the authors determined the structure of PS1 CTF. The structure fits well with previous studies using cysteine accessibility methods by us and by Bart de Strooper’s group. This is important because it is a first structure of a part of PS1 resolved at the atomic level. The study’s potential impact could come from an intriguing feature it shows around catalytic aspartate residue 385, that is, a half helix and extended structure kinked by a glycine residue located near the aspartate. This supports the notion that intramembrane cleavage is occurring within the water-accessible pore structure in the membrane.

At the same time, further study (e.g., using holoprotein) is required, as the PS1 N-terminal fragment (NTF) is also required for the proteolytic activity. Moreover, we have identified that TMD1 of PS1 also faces the catalytic pore (Takagi et al., unpublished result), suggesting that several TMDs in NTFs are involved in the formation of the catalytic pore.

Without an atomic structure, it is impossible to “rationally design” inhibitors or modulators. The Doetsch paper is a first step toward understanding the process by γ-secretase at an atomic level. The field has encountered difficulties for structural studies of this unusual membrane-bound protease; however, we also know that tackling this issue by whatever means provides hope for the future.

View all comments by Taisuke Tomita