. An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 PubMed.


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  1. Shi and colleagues delight us with the first atomic view of the γ-secretase complex!

    The atomic model shows many interesting features, but what I find most provocative and exciting is the plasticity/flexibility implied by this static view to make the structure compatible with an active and highly allosteric protease. Clearly, this is the model of an inactive γ-secretase complex that must go through extensive conformational changes to bring the catalytic Aspartate residues, located more than 10Å from each other, into hydrogen bonding distance. This snapshot thus highlights how important protein conformational changes are in the γ-secretase complex, which very well supports the view that γ-secretase exists as an ensemble of multiple conformations and that their equilibrium is functionally relevant (Elad et al., 2015).

    Furthermore, the active site of PS1 is accessible from the convex side of the transmembrane (TM) horseshoe, while the putative substrate binding pocket (Glu333) in the nicastrin extracellular domain (ECD) actually faces the concave side. Participation of the nicastrin ECD in substrate recruitment, as proposed by Shah et al., would require a large conformational rearrangement in the complex (Shah et al., 2005). However, it should be kept in mind that the nicastrin-substrate interaction model remains controversial, as it has been challenged by two independent groups (Chavez-Gutierrez et al., 2008; Zhao et al., 2010). The new atomic model will probably guide experimentalists to further resolve this controversial issue. 

    The reported atomic structure places about two-thirds of the residues mutated in familial Alzheimer disease (FAD) in two “hotspots” in PSEN1, each located at the inner core of a four-TM bundle (just a note: several FAD-linked mutations have been identified in TM1). How mutations in these hotspots translate into the common kinetic mechanism (impaired carboxypeptidase-like activity) observed for FAD-linked mutations (Chavez-Gutierrez et al., 2012) awaits further investigation. I am certain that the atomic model will serve as a structural frame for this task. 

    Finally, I would like to emphasize that the activity data provided by Shi and colleagues on FAD-linked mutations confirms that total γ-secretase loss of function is not commonly observed among disease-causing mutants (Chavez-Gutierrez et al., 2012) and therefore it cannot be the basis of the pathogenic mechanism.


    . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.

    . Glu(332) in the Nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity. J Biol Chem. 2008 Jul 18;283(29):20096-105. PubMed.

    . The dynamic conformational landscape of gamma-secretase Nadav. J Cell Sci. 2015 Feb 1;128(3):589-98. PubMed.

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

    . Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. J Neurosci. 2010 Feb 3;30(5):1648-56. PubMed.

    View all comments by Lucia Chavez-Gutierrez
  2. This paper by Drs. Scheres, Shi, and colleagues represents a milestone in research on the structural biology of γ-secretase. They have utilized an impressive array of methodologies that took tremendous effort. This study provides several molecular insights into the unique intramembrane protease.

    The structure fits very well with previous biochemical analyses in regard to intratransmembrane domains and intermolecule associations. They also confirmed novel intimate interactions by cross-linking methodologies. While we know we have an accurate global structure for γ-secretase, we await the structure within the lipid bilayer. It is well known that the composition of lipids in the bilayer also affects the enzymatic activity. Consistent with this, the researchers found phospholipids embedded in the γ-secretase complex. It would be very interesting to test whether these lipids are essential for γ-secretase structure and activity in a similar manner to that observed for several channels and receptors (reviewed in Cornelius et al., 2015; Taberner et al., 2015).

    Their study also highlights a yet-unsolved issue of the γ-secretase: structural dynamics during the endoproteolysis. We and others have reported conformational changes of the γ-secretase by biochemical experiments (Takeo et al., 2012; Takagi-Niidome et al, 2013; Takeo et al., 2014; Takagi-Niidome et al., 2015). Intriguingly, structures of some parts of PS (i.e., N-terminal region, TMD2, Loop 1, Loop 6) have not been resolved in this new structure. Also, the distance of the catalytic aspartates is farther than that of activated aspartic proteases. Further structural analysis of γ-secretase with inhibitors/modulators and molecular dynamics simulation would provide novel insights into the mechanistic action of the intramembrane proteolysis.


    . General and specific lipid-protein interactions in Na,K-ATPase. Biochim Biophys Acta. 2015 Sep;1848(9):1729-43. Epub 2015 Mar 16 PubMed.

    . TRP channels interaction with lipids and its implications in disease. Biochim Biophys Acta. 2015 Sep;1848(9):1818-27. Epub 2015 Mar 30 PubMed.

    . Contribution of the γ-secretase subunits to the formation of catalytic pore of presenilin 1 protein. J Biol Chem. 2012 Jul 27;287(31):25834-43. Epub 2012 Jun 11 PubMed.

    . Inhibition of γ-secretase activity by a monoclonal antibody against the extracellular hydrophilic loop of presenilin 1. Biochemistry. 2013 Jan 8;52(1):61-9. Epub 2012 Dec 14 PubMed.

    . Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10544-9. Epub 2014 Jul 9 PubMed.

    . Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of γ-secretase. J Neurosci. 2015 Feb 11;35(6):2646-56. PubMed.

    View all comments by Taisuke Tomita
  3. This study by Bai and colleagues resolves the γ-secretase structure to an atomic level (resolution of 3.4Ǻ). This type of detail allows the authors to map and analyze some of the reported PSEN1 disease-associated mutations and to start to develop clearer ideas about the mechanisms of the mutations. As predicted in an earlier study (Hardy and Crook, 2001), many of the mutations align along transmembrane (TM) helical faces. Bai and colleagues now analyzed 35 residues in the TMs that correspond to 101 Alzheimer’s mutations, and identified two mutational hotspots in TMs 2-5 and 6-9. In both cases the affected residues have their side chains facing the inner core of the TMs, with only one side of each TM helix being affected.

    This structural resolution of PSEN1 yields information that can be used when assessing pathogenicity of novel variants identified in the gene. We have previously proposed a decision tree, where the location of the variants influenced the prediction of pathogenicity (Guerreiro et al., 2010). When a new variant is identified, it should be modeled using this high-resolution structure to help in the decision regarding its pathogenicity.

    Bai and colleagues show that the mutations do not cause a consistent change in the protease activity of γ-secretase.  In fact, this was already known from biochemical analysis of the effects of presenilin mutations on γ-secretase (Chavez-Gutierrezet al. 2012). Whether this detailed knowledge of γ-secretase structure will lead to more or less work on developing inhibitors and modulators of this complex is debatable (De Strooper, 2014). And we have to remember that there are many different γ-secretases based on different presenilins, different APHs, and different splice forms of the enzyme. Clearly, therefore, this is a great step forward, but much more needs to be done.


    . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.

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

    . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

    . Presenilin mutations line up along transmembrane alpha-helices. Neurosci Lett. 2001 Jun 29;306(3):203-5. PubMed.

    View all comments by John Hardy
  4. I agree with Sam Sisodia that assessing the structure of other mutations would be useful. An obvious one is the D9 mutation which has a clear effect on function (Perez-Tur et al., 1995; Thinakaran et al., 1996).


    . A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport. 1995 Dec 29;7(1):297-301. PubMed.

    . Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996 Jul;17(1):181-90. PubMed.

    View all comments by John Hardy

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