. Structural basis of human γ-secretase assembly. Proc Natl Acad Sci U S A. 2015 May 12;112(19):6003-8. Epub 2015 Apr 27 PubMed.


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  1. I read with great interest this report from Yigong Shi's group. It reveals unexpected features of the γ-secretase structure and it raises many questions about the structure-function relationships in the protease complex, as many other excellent studies have. Most remarkably, the intimate connection between PSEN C-terminal fragment and APH1 is very intriguing. Our previous studies points to APH1 as an allosteric subunit in the complex (Acx et al., 2013). That APH1 and PSEN form the protease core and share a large interface may provide the structural basis for the functional effect. I also find intriguing the poor electron densities observed for PSEN1 TM6 and TM2, as discussed by the authors, as this could be an indication of their participation in substrate gating/entry.

    Definitively, the structural model presented in this study is a valuable framework to project and understand previous experimental observations as well as to design further experimental work to decipher the mechanisms of γ-secretase and “assimilate” them into a full view of γ-secretase structure/function.

    Finally, I would like to say that the outstanding contribution of the Yigong Shi and colleagues to the field makes this a very exciting time for everyone sharing a fascination for γ-secretase!


    . Signature amyloid β profiles are produced by different γ-secretase complexes. J Biol Chem. 2014 Feb 14;289(7):4346-55. Epub 2013 Dec 13 PubMed.

  2. Structural details of the γ-secretase complex had remained elusive, until last year when Yigong Shi and colleagues solved the structure of human γ-secretase by cryo-EM (Lu et al., 2014). This structure revealed the overall architecture of the complex, with the ectodomain of nicastrin sitting on top of a horseshoe-shaped structure composed of the transmembrane domains (TMDs) of the catalytic component presenilin and those of the other γ-secretase subunits—Pen2, Aph1, and nicastrin, which has one TMD incorporated into the horseshoe. While the solution of this structure (at an overall resolution of 4.5 angstroms) provided a huge leap forward in our understanding of γ-secretase, the limited resolution of the TMDs (range of 5-7 angstroms) prevented accurate assignment of each TMD to each of the four γ-secretase components.

    In this latest advance, Sun et al.  were able to obtain a higher-resolution image of the TMDs of the complex, again using cryo-EM. The better overall resolution (4.32 angstroms)—along with the fusion of T4 lysozyme to the N-terminus of presenilin— led to what is very likely the proper assignment of each of the TMDs of all four γ-secretase components. The new assignment of the nine presenilin TMDs reveals a close match in fold with that of an archaeal presenilin homolog solved two years ago by the Shi group (Li et al., 2013). With this increased resolution and thus clearer assignment of each of the TMDs come two main surprises: the di-aspartyl active site of presenilin lies on the convex side of the horseshoe, not within the concave cleft as originally presumed; and Pen2 contains not two but three TMDs, with one of the original two dipping only halfway into the membrane region before doing a hairpin turn.  Thus, the total number of TMDs in the γ-secretase complex is increased from 19 to 20.

    Now that the overall architecture of the complex is known, the atomic details of the TMDs need to be resolved. This would provide essential clues to the mechanism(s) by which mutations in presenilin found in familial Alzheimer’s disease (FAD) patients affect amyloid precursor protein processing. Such information should facilitate the development of modulators of γ-secretase as potential AD therapeutics, an area that has received less attention than it should (De Strooper et al., 2014; Feb 2015 news).


    . Three-dimensional structure of human γ-secretase. Nature. 2014 Aug 14;512(7513):166-70. Epub 2014 Jun 29 PubMed.

    . Structure of a presenilin family intramembrane aspartate protease. Nature. 2013 Jan 3;493(7430):56-61. PubMed.

    . Lessons from a failed γ-secretase Alzheimer trial. Cell. 2014 Nov 6;159(4):721-6. PubMed.

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  1. Gamma Secretase: Intramembrane Liaisons Revealed