Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis
Citation
Chen, 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.Abstract
Many 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687875/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662212
Collections
- FAS Scholarly Articles [18292]
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)