Chen AC, Kim S, Shepardson N, Patel S, Hong S, Selkoe DJ. Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis. J Cell Biol. 2015 Dec 21;211(6):1157-76. PubMed.
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University Kiel
This study certainly contains a huge amount of biochemical and microscopy data supporting a close interaction between the γ-secretase complex and α-secretase and between γ- and β-secretases. As the authors point out, several γ-secretase interactome studies did not identify ADAM10 (aka α-secretase), suggesting an indirect association (this is also true the other way around … for α-secretase interactome studies). The authors explain that tetraspanins, which are known to be essential for ADAM10 and γ-secretase activity, are possible mediators of these interactions. I would assume that these super secretase complexes are part of the tetraspanin web and that this secretase-secretase interaction helps determine the assembly of the super complex, its half-life, its activity, and its substrate handling.
There are—as always—numerous questions raised by this study, including how cleavage is regulated in such webs, what are the components of these complexes in human neurons, when are the complexes formed, and how they are intracellularly transported. Is such an assembly of a membrane protease complex and substrates also relevant for other proteases? The role of the γ-secretase complexes could also be analyzed in genetic models, and it would be nice to clarify their function(s) in a more physiological context.
View all comments by Paul SaftigUK Dementia Research Institute@UCL and VIB@KuLeuven
The paper of Chen and co-authors is highly interesting, supporting the concept that γ-secretases interact with α- and β-secretases and that the enzymes are clustered in specific subdomains in the cellular membranes. It remains to be sorted out to what extent the different γ-secretase complexes behave similarly, how many different combinations of proteases and, why not, of specific substrates, are possible in these membrane microdomains. A dynamic clustering of proteases and substrates like APP, Notch, N-Cadherin in multimolecular complexes in the plane of the membrane might actually provide specificity and regulation to γ-secretase processing (De Strooper and Annaert, 2010); contradicting the dogmatic view in the field that γ-secretases cleave by default many different substrates in an unregulated way.
This view has frightened the pharmaceutical industry (and funders of AD research) because of the potential side effects when globally inhibiting these activities. However, the work here, together with other work showing differential expression and activity of the different complexes and regulation of their activity by membrane compartmentalization (see Vetrivel et al., 2005; Thathiah et al., 2013), shows that much still has to be learned.
Tetraspanins, as suggested in this work but also before, might play a central role in the regulation of γ-secretase substrate specificity by compartmentalization of the enzymes in membrane microdomains (Wakabayashi et al., 2009; Dunn et al., 2010). Understanding this intriguing compartmentalization in the context of the cell will teach us that these enzymes have very precise functions. Targeting these complexes specifically is an important aim for drug discovery in the next decade.
References:
De Strooper B, Annaert W. Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu Rev Cell Dev Biol. 2010 Nov 10;26:235-60. PubMed.
Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, Parent AT, Sisodia SS, Thinakaran G. Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J Biol Chem. 2005 Jul 8;280(27):25892-900. PubMed.
Thathiah A, Horré K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M, De Kloe G, Munck S, De Strooper B. β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat Med. 2013 Jan;19(1):43-9. PubMed.
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.
Dunn CD, Sulis ML, Ferrando AA, Greenwald I. A conserved tetraspanin subfamily promotes Notch signaling in Caenorhabditis elegans and in human cells. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5907-12. Epub 2010 Mar 10 PubMed.
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