. Crystal structure of the γ-secretase component nicastrin. Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13349-54. Epub 2014 Sep 2 PubMed.


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  1. In this study, Xie et al. tell us a structural tale of two lobes with the atomic resolution structure of nicastrin, the largest component of γ-secretase. Here, the ectodomain (ECD) of nicastrin from Dictyostelium purpureum, whose γ-secretase can faithfully process human APP (McMains et al., 2010), was expressed, purified, and crystalized. The structure of the ECD crystal was then solved at 1.95Å. Xie et al. showed that nicastrin contains one large lobe and one small, with each containing smaller structural domains. These two lobes are held together by multiple hydrogen bonds and Van der Waals interactions. A pocket surrounded by hydrophilic residues is located in the large lobe, which is speculated to be the binding site for γ-secretase substrates. A short loop extending out from the small lobe covers this pocket, seemingly a lid for this potential substrate binding site.

    Based on the above information, Xie et al. also refined the 4.5 Å human nicastrin structural model, which was reported by the same research group earlier this year through cryo-electron-microscopy single-particle analysis (Lu et al., 2014). They showed that human and Dictyostelium purpureum nicastrins share many highly conserved structures, including the bilobed overall structure, similar H-bonds and Van der Waals interactions between the two lobes, a speculated substrate binding pocket in the large lobe and a lid covering this pocket. In addition, they redefined the relative positions of other components in γ-secretase.

    In this structure model, since the lid blocks the potential substrate-binding pocket, they speculated that the model represents an inactive form of nicastrin. In order for nicastrin to capture substrate, Xie et al. propose that the lid could be removed through the relative rotation of the large and small lobes.   

    This nicastrin structural model clearly supports previous reports that γ-secretase accesses its substrates through nicastrin (Shah et al., 2005; Dries et al., 2009; Zhang et al., 2012). Knowing the positions of those residues surrounding the pocket in the large lobe will help to design experiments to further confirm the function of this pocket. The unexpected lid structure is another interesting discovery. Does the lid serve simply as a switch to convert nicastrin between inactive and active conformation? Or, does it also play other roles in recruiting substrates? After all, there is a long list of substrates trying to access γ-secretase through this binding site. Understanding how the lid functions will help elucidate how nicastrin recruits substrates. As another potential therapeutic target in addition to presenilin, the accurate structural information for nicastrin will certainly contribute to new ideas for modulating γ-secretase activity. This study, together with the EM study on γ-secretase complex, undoubtedly advanced our knowledge of the structure of this important enzyme.


    . Dictyostelium possesses highly diverged presenilin/gamma-secretase that regulates growth and cell-fate specification and can accurately process human APP: a system for functional studies of the presenilin/gamma-secretase complex. Dis Model Mech. 2010 Sep-Oct;3(9-10):581-94. PubMed.

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

    . Nicastrin functions as a gamma-secretase-substrate receptor. Cell. 2005 Aug 12;122(3):435-47. PubMed.

    . Glu-333 of nicastrin directly participates in gamma-secretase activity. J Biol Chem. 2009 Oct 23;284(43):29714-24. PubMed.

    . Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8534-9. PubMed.

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  1. Crystal Structure Suggests Nicastrin Binds γ-Secretase Substrates