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Wakabayashi T, Craessaerts K, Bammens L, Bentahir M, Borgions F, Herdewijn P, Staes A, Timmerman E, Vandekerckhove J, Rubinstein E, Boucheix C, Gevaert K, De Strooper B. Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat Cell Biol. 2009 Nov;11(11):1340-6. PubMed.
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University of Zurich
Another beautiful work on the biochemistry of γ-secretase complex from the group of Bart de Strooper.
This connection to tetraspanins offers key insights into the "raft"
association of γ-secretase. The raft link to APP processing is very weak and highly contended. Lipid rafts are dynamic platforms that could be, to a large extent, biochemically purified by detergent extraction methods.
Typically Triton X-100 (in concentration ranging from 0.3 percent to 1 percent) insoluble fractions of membranes represent the raft fraction. However, tetraspanin microdomains (TEM) differ from the "canonical" rafts in that these are triton soluble but are insoluble to other milder detergents such as CHAPS or BRIJ. This study clearly demonstrates a direct link between tetraspanin microdomains and γ-secretase, thereby providing evidence that much of the γ-secretase activity is probably confined to tetraspanin microdomains.
An (obvious) interesting question is, How about Notch cleavage? While γ-secretase cleavage of β-CTF seems to depend on its interaction with the tetraspanin web, it would be interesting to see if there is a lateral compartmentalization in γ-secretase (non-TEM vs. TEM γ-complexes) that could determine substrate specificity. In my opinion, this systematic interactome analysis elegantly shows that Aβ production, though primarily achieved by only three players (APP, BACE1, and γ-secretase complex), is far too complex in the cellular context.
University of Kansas
This is an excellent study by the De Strooper lab, using a biochemical approach to identify proteins that associate with the γ-secretase complex. The work was rigorously done, with important controls to identify interactions specific to γ-secretase (e.g., parallel purification of the presenilin-like protease SPPL3). The authors confirm several proteins previously reported to interact with γ-secretase, such as TMP21, β-catenin and Rab11, further strengthening confidence in their method. Most interesting was the identification of tetraspanin proteins, which are important in many basic cellular activities, including formation of certain lipid raft-like microdomains. Indeed, γ-secretase components co-distribute with tetraspanin proteins in a sucrose density gradient.
Knockdown of certain associated tetraspanin-web proteins by RNAi led to modest but significant decreases in amyloid-β-protein levels and increases in APP C-terminal fragments that are γ-secretase substrates. Conversely, overexpression can lead to increased amyloid production.
Overall, these findings are important contributions to our understanding of the cell biology of γ-secretase, identifying partner proteins that can modulate protease activity and affect amyloid production. Going forward, it will be worthwhile to investigate possible roles of tetraspanin genes in the pathogenesis of AD or whether the levels of the encoded proteins are otherwise altered. Targeting tetraspanins to prevent or treat AD, however, is probably not advised, because these proteins affect other γ-secretase-mediated proteolytic events (syndecan-3, N-cadherin, APLP-2, and ADAM10, shown in this new report); they are probably also critical for Notch proteolysis and signaling. Inhibition of Notch signaling leads to toxic effects that must be avoided in targeting γ-secretase, whether directly or indirectly, for AD.
Medical University of South Carolina
This represents a careful and significant study with clean results. It probably explains why γsecretase loses activity in Triton-X100 and helps in a more thorough functional characterization of the enzyme.
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