dc.contributor.author | Chen, Allen C. | en_US |
dc.contributor.author | Kim, Sumin | en_US |
dc.contributor.author | Shepardson, Nina | en_US |
dc.contributor.author | Patel, Sarvagna | en_US |
dc.contributor.author | Hong, Soyon | en_US |
dc.contributor.author | Selkoe, Dennis J. | en_US |
dc.date.accessioned | 2016-07-14T19:16:57Z | |
dc.date.issued | 2015 | en_US |
dc.identifier.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. | en |
dc.identifier.issn | 0021-9525 | en |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662212 | |
dc.description.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. | en |
dc.language.iso | en_US | en |
dc.publisher | The Rockefeller University Press | en |
dc.relation.isversionof | doi:10.1083/jcb.201502001 | en |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687875/pdf/ | en |
dash.license | LAA | en_US |
dc.subject | Article | en |
dc.title | Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis | en |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en |
dc.relation.journal | The Journal of Cell Biology | en |
dash.depositing.author | Patel, Sarvagna | en_US |
dc.date.available | 2016-07-14T19:16:57Z | |
dc.identifier.doi | 10.1083/jcb.201502001 | * |
dash.contributor.affiliated | Hong, Soyon | |
dash.contributor.affiliated | Patel, Sarvagna | |
dash.contributor.affiliated | Selkoe, Dennis | |