Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis
| Autor: | Sarvagna Patel, Dennis J. Selkoe, Nina E. Shepardson, Allen C. Chen, Soyon Hong, Sumin Kim |
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| Rok vydání: | 2015 |
| Předmět: |
Immunoprecipitation
Proteolysis ADAM10 CHO Cells Models Biological Regulated Intramembrane Proteolysis Article Cell membrane Mice Cricetulus Tetraspanin medicine Animals Humans Cells Cultured Research Articles medicine.diagnostic_test biology Cell Membrane Cell Biology Transmembrane protein Cell biology Mice Inbred C57BL medicine.anatomical_structure Biochemistry biology.protein Amyloid Precursor Protein Secretases Amyloid precursor protein secretase |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.201502001 |
| Popis: | The α-secretase ADAM10 interacts with γ-secretase in a proteolytically functional complex, which may suggest a new mechanism of RIP signaling where the sheddase and intramembrane protease reside together in a complex that can accept and process full-length substrates efficiently. 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. |
| Databáze: | OpenAIRE |
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