| First Author | Chen AC | Year | 2015 |
| Journal | J Cell Biol | Volume | 211 |
| Issue | 6 | Pages | 1157-76 |
| PubMed ID | 26694839 | Mgi Jnum | J:230836 |
| Mgi Id | MGI:5766116 | Doi | 10.1083/jcb.201502001 |
| Citation | Chen AC, et al. (2015) Physical and functional interaction between the alpha- and gamma-secretases: A new model of regulated intramembrane proteolysis. J Cell Biol 211(6):1157-76 |
| abstractText | Many single-transmembrane proteins are sequentially cleaved by ectodomain-shedding alpha-secretases and the gamma-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 alpha- and gamma-secretase. ADAM10 (A10), the principal neuronal alpha-secretase, interacted and cofractionated with gamma-secretase endogenously in cells and mouse brain. A10 immunoprecipitation yielded gamma-secretase proteolytic activity and vice versa. In agreement, superresolution microscopy showed that portions of A10 and gamma-secretase colocalize. Moreover, multiple gamma-secretase inhibitors significantly increased alpha-secretase processing (r = -0.86) and decreased beta-secretase processing of beta-amyloid precursor protein. Select members of the tetraspanin web were important both in the association between A10 and gamma-secretase and the gamma --> alpha feedback mechanism. Portions of endogenous BACE1 coimmunoprecipitated with gamma-secretase but not A10, suggesting that beta- and alpha-secretases can form distinct complexes with gamma-secretase. Thus, cells possess large multiprotease complexes capable of sequentially and efficiently processing transmembrane substrates through a spatially coordinated RIP mechanism. |
