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

Rosanne Wouters, Christine Michiels, Ragna Sannerud, Bertrand Kleizen, Katleen Dillen, Wendy Vermeire, Abril Escamilla Ayala, David Demedts, Randy Schekman, Wim Annaert*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article numbere201911104
Pages (from-to)1-26
JournalJournal of Cell Biology
Volume220
Issue number9
DOIs
Publication statusPublished - 22 Jul 2021

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

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