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Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum

Authors :
Wim Annaert
Katleen Dillen
Randy Schekman
Ragna Sannerud
Bertrand Kleizen
Rosanne Wouters
David Demedts
Christine Michiels
Abril Escamilla Ayala
Wendy Vermeire
Source :
Journal of Cell Biology, 220(9), 1. Rockefeller University Press
Publication Year :
2021
Publisher :
Rockefeller University Press, 2021.

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 post-Golgi compartments. ispartof: JOURNAL OF CELL BIOLOGY vol:220 issue:9 ispartof: location:United States status: published

Details

ISSN :
15408140 and 00219525
Volume :
220
Database :
OpenAIRE
Journal :
Journal of Cell Biology
Accession number :
edsair.doi.dedup.....09d9039d96590f096bfacb0662aeabdb
Full Text :
https://doi.org/10.1083/jcb.201911104