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Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis
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.
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Interactions between APP and canonical secretases result in multifunctional APP derivatives.
“The complexity of interactions between APP and canonical secretases results in multifunctional derivatives of APP (Chen et al., 2015; Liu et al., 2019).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Chen et al., 2015
Aη-γ peptides were not detected, probably revealing a lack of functional interaction between η- and γ-secretase.
“Aη-γ peptides, potentially generated by a combined action of MT5-MMP and γ-secretase, were not detected, probably revealing a lack of functional interaction between η- and γ-secretase as it is the case with BACE-1, ADAM10 and γ-secretase (Chen et al., 2015; Liu et al., 2019).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Chen et al., 2015
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Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089
Amyloid β-peptide is produced by cultured cells during normal metabolism
Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., Teplow, D. B., et al. (1992) · Nature · doi:10.1038/359322a0 · Cited by 1,921
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“Surface-biotinylated and control cell lysates were enriched for intact γ-secretase by IP of Aph-1, an early member in γ-complex assembly (LaVoie et al., 2003).”
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Cited by
Sorted by citations
García-González, L., Pilat, D., Baranger, K., & Rivera, S. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00244 · Cited by 88
Eggert, S., Kins, S., Endres, K., & Brigadski, T. (2022) · Biological Chemistry · doi:10.1515/hsz-2021-0330 · Cited by 46
Metadata
- Authors
- Chen, A. C., Kim, S., Shepardson, N., Patel, S., Hong, S., & Selkoe, D. J.
- Affiliations
- Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 1
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115 2
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2015-12-21
- Volume
- 211
- Issue
- 6
- Pages
- 1157-1176
- ISSN
- 0021-9525
- 1540-8140
- PMC
- PMC4687875
- Cited by
- 62
- References
- 4
- Language
- en
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