Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum
Publication date
2021-07-22
Authors
Wouters, Rosanne
Michiels, Christine
Sannerud, Ragna
Kleizen, Bertrand
Dillen, Katleen
Vermeire, Wendy
Ayala, Abril Escamilla
Demedts, David
Schekman, Randy
Annaert, Wim
Editors
Advisors
Supervisors
Document Type
Article
Metadata
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License
cc_by_nc_sa
Abstract
γ-Secretase affects many physiological processes through targeting >100 substrates; malfunctioning links γ-secretase to cancer and Alzheimer’s disease. The spatiotemporal regulation of its stoichiometric assembly remains unresolved. Fractionation, biochemical assays, and imaging support prior formation of stable dimers in the ER, which, after ER exit, assemble into full complexes. In vitro ER budding shows that none of the subunits is required for the exit of others. However, knockout of any subunit leads to the accumulation of incomplete subcomplexes in COPII vesicles. Mutating a DPE motif in presenilin 1 (PSEN1) abrogates ER exit of PSEN1 and PEN-2 but not nicastrin. We explain this by the preferential sorting of PSEN1 and nicastrin through Sec24A and Sec24C/D, respectively, arguing against full assembly before ER exit. Thus, dimeric subcomplexes aided by Sec24 paralog selectivity support a stepwise assembly of γ-secretase, controlling final levels in postGolgi compartments.
Keywords
Amyloid Precursor Protein Secretases/chemistry, Animals, Biological Transport, COP-Coated Vesicles/chemistry, Cell Line, Cell Line, Tumor, Cerebral Cortex/cytology, Endopeptidases/chemistry, Endoplasmic Reticulum/metabolism, Fibroblasts/cytology, Gene Expression Regulation, Golgi Apparatus/metabolism, Humans, Membrane Proteins/chemistry, Mice, Models, Molecular, Neurons/cytology, Presenilin-1/chemistry, Primary Cell Culture, Protein Binding, Protein Conformation, Protein Isoforms/chemistry, Protein Multimerization, Rats, Rats, Wistar, Signal Transduction, Vesicular Transport Proteins/genetics, SDG 3 - Good Health and Well-being
Citation
Wouters, R, Michiels, C, Sannerud, R, Kleizen, B, Dillen, K, Vermeire, W, Ayala, A E, Demedts, D, Schekman, R & Annaert, W 2021, 'Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum', Journal of Cell Biology, vol. 220, no. 9, e201911104, pp. 1-26. https://doi.org/10.1083/jcb.201911104