Chen, Allen C.Kim, SuminShepardson, NinaPatel, SarvagnaHong, SoyonSelkoe, Dennis2016-07-142015Chen, Allen C., Sumin Kim, Nina Shepardson, Sarvagna Patel, Soyon Hong, and Dennis J. Selkoe. 2015. “Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis.” The Journal of Cell Biology 211 (6): 1157-1176. doi:10.1083/jcb.201502001. http://dx.doi.org/10.1083/jcb.201502001.0021-9525http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662212Many single-transmembrane proteins are sequentially cleaved by ectodomain-shedding α-secretases and the γ-secretase complex, a process called regulated intramembrane proteolysis (RIP). These cleavages are thought to be spatially and temporally separate. In contrast, we provide evidence for a hitherto unrecognized multiprotease complex containing both α- and γ-secretase. ADAM10 (A10), the principal neuronal α-secretase, interacted and cofractionated with γ-secretase endogenously in cells and mouse brain. A10 immunoprecipitation yielded γ-secretase proteolytic activity and vice versa. In agreement, superresolution microscopy showed that portions of A10 and γ-secretase colocalize. Moreover, multiple γ-secretase inhibitors significantly increased α-secretase processing (r = −0.86) and decreased β-secretase processing of β-amyloid precursor protein. Select members of the tetraspanin web were important both in the association between A10 and γ-secretase and the γ→α feedback mechanism. Portions of endogenous BACE1 coimmunoprecipitated with γ-secretase but not A10, suggesting that β- and α-secretases can form distinct complexes with γ-secretase. Thus, cells possess large multiprotease complexes capable of sequentially and efficiently processing transmembrane substrates through a spatially coordinated RIP mechanism.en-USArticleJournal Article2016-07-1410.1083/jcb.201502001