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Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum
- 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
- Subjects :
- Models, Molecular
Endopeptidases/chemistry
Protein Conformation
Vesicular Transport Proteins
Wistar
Golgi Apparatus
Endoplasmic Reticulum
Mice
Neurons/cytology
0302 clinical medicine
COP-Coated Vesicles/chemistry
Models
COMPLEX COMPONENT
PSEN1
Protein Isoforms
Endoplasmic Reticulum/metabolism
COPII
Cerebral Cortex
Neurons
Golgi Apparatus/metabolism
0303 health sciences
Budding
Tumor
biology
MEMBRANE-PROTEINS
Vesicle
ER RETENTION
Cell biology
AMYLOID PRECURSOR PROTEIN
ALZHEIMERS-DISEASE
COP-Coated Vesicles
Life Sciences & Biomedicine
Cerebral Cortex/cytology
Protein Binding
Signal Transduction
STRUCTURAL BASIS
COPII VESICLES
PRESENILIN-1
Protein subunit
Primary Cell Culture
Protein Isoforms/chemistry
Nicastrin
Amyloid Precursor Protein Secretases/chemistry
Presenilin
Cell Line
Vesicular Transport Proteins/genetics
03 medical and health sciences
QUALITY-CONTROL
Cell Line, Tumor
Presenilin-1/chemistry
Endopeptidases
Presenilin-1
Animals
Humans
Rats, Wistar
030304 developmental biology
Science & Technology
Endoplasmic reticulum
Membrane Proteins
Molecular
Membrane Proteins/chemistry
Biological Transport
Cell Biology
Fibroblasts
Rats
Fibroblasts/cytology
Gene Expression Regulation
biology.protein
INTERMEDIATE COMPARTMENT
Amyloid Precursor Protein Secretases
Protein Multimerization
030217 neurology & neurosurgery
Subjects
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